Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage. The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury. Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury, suggesting that this axis is a novel target and regulatory control point for treatment. This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis, along with the regenerative and repair mechanisms linking the axis to spinal cord injury. Additionally, we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis. This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs, along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs. Nevertheless, there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis. This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.

The transition in terminology from fatty liver disease to metabolic dysfunction-associated steatotic liver disease (MASLD) marks a considerable evolution in diagnostic standards. This new definition focuses on liver fat accumulation in the context of overweight/obesity, type 2 diabetes, or metabolic dysfunction, without requiring the exclusion of other concurrent liver diseases. The new definition also provides clear guidelines for defining alcohol consumption in relation to the disease. MASLD is currently acknowledged as the most widespread liver disorder globally, affecting ~25% of the population. Despite the extensive array of clinical trials conducted in recent years, the number of approved treatments for metabolic dysfunction-associated fatty liver disease is very limited. In the review critically evaluates the results of clinical trials of related drugs and assesses the future directions for drug development trials. The renaming of MASLD presents new challenges and opportunities for the design of clinical trials and the selection of target populations for drug development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous disease caused by multiple etiologies. It is characterized by excessive fat accumulation in the liver. Without intervention, MASLD can progress from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and even to cirrhosis and hepatocellular carcinoma. However, the pathogenesis of MASH and the mechanism underlying the development of fibrosis remain poorly understood, posing challenges for accurate diagnosis of MASH and fibrosis. In this study, we analyzed tissue RNA-seq data and clinical information of healthy individuals and MASLD patients from multiple datasets, the key genes and pathways involved in the occurrence and progression of MASLD, MASH, and fibrosis were screened respectively. Our findings reveal that the development of MASLD, MASH and fibrosis is associated with lipid metabolism processes. Based on the RNA expression profiles of identified hub genes, we established three alternative diagnostic models for MASLD, MASH, and fibrosis. These models demonstrated excellent performance in the diagnosis of MASLD, MASH, and fibrosis, with AUC values exceeding 0.9, implicating its potential clinical values in disease diagnosis.

Liver fibrosis is a common response to chronic liver injury due to multiple etiologies and plays a crucial in the progression of chronic liver disease to cirrhosis, hepatocellular carcinoma, and other liver-related clinical outcomes. Currently, available treatments to block liver fibrosis are designed to eliminate the underlying causes of liver disease. The lack of truly effective drugs to regress or reverse fibrosis is a major unmet clinical need. In this context, this article briefly describes the pathological process of hepatic fibrosis and focuses on reviewing the progress of clinical studies on mechanism-based anti-fibrotic drug development and therapy, highlighting that the positive effect of thyroid hormone receptor-β (THR-β) analogs, fibroblast growth factor 21 (FGF21) analogues, Glucagon-like peptide 1 receptor (GLP-1R) agonists, pan-peroxisome proliferator-activated receptor (pan-PPAR) agonists, fatty acid synthase (FASN) inhibitors, and hydronidone in reducing liver fibrosis caused by specific etiologies. Moreover, multi-pathway guided combination therapy or traditional Chinese medicine demonstrate significant advantages in combating liver fibrosis. Finally, new technologies and approaches affecting the clinical development of anti-hepatic fibrosis drugs were discussed.

The liver is a central metabolic organ, but is also hosting a unique immune microenvironment to sustain homeostasis and proper defense measures against injury threats in healthy individuals. Liver macrophages, mostly represented by the tissue-resident Kupffer cells and bone marrow- or monocyte-derived macrophages, are intricately involved in various aspects of liver homeostasis and disease, including tissue injury, inflammation, fibrogenesis and repair mechanisms.

We review recent findings on defining the liver macrophage landscape and their functions in liver diseases with the aim of highlighting potential targets for therapeutic interventions. A comprehensive literature search in PubMed and Google Scholar was conducted to identify relevant literature up to date.

Liver macrophages orchestrate key homeostatic and pathogenic processes in the liver. Thus, targeting liver macrophages represents an attractive strategy for drug development, e.g. to ameliorate liver inflammation, steatohepatitis or fibrosis. However, translation from fundamental research to therapies remains challenging due to the versatile nature of the liver macrophage compartment. Recent and major technical advances such as single-cell and spatially-resolved omics approaches deepened our understanding of macrophage biology at a molecular level. Yet, further studies are needed to identify suitable, etiology- and stage-dependent strategies for the treatment of liver diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a series of obesity-related metabolic liver diseases, ranging from relatively benign hepatic steatosis to metabolic-associated steatohepatitis (MASH). With the changes in lifestyle, its incidence and prevalence have risen to epidemic proportions globally. In recent years, an increasing amount of evidence has indicated that the hepatic microenvironment is involved in the pathophysiological processes of MASH-induced liver fibrosis and the formation of hepatocellular carcinoma (HCC). The hepatic microenvironment is composed of various parenchymal and non-parenchymal cells, which communicate with each other through various factors. In this review, we focus on the changes in hepatocytes, cholangiocytes, liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), Kupffer cells (KC), dendritic cells (DC), neutrophils, monocytes, T and B lymphocytes, natural killer cells (NK), natural killer T cells (NKT), mucosal-associated invariant T cells (MAIT), γδT cells, and gut microbiota during the progression of MASLD. Furthermore, we discuss promising therapeutic strategies targeting the microenvironment of MASLD-MASH-HCC.

The incidence of nonalcoholic steatohepatitis (NASH) is increasing annually, posing a significant threat to human health. NASH is typified by hepatic steatosis, inflammation, and hepatocellular injury, frequently culminating in fibrosis and cirrhosis. Yet, the precise pathogenesis of NASH remains to be fully elucidated. The hepatic sinusoid, which serves as the fundamental structural and functional unit of the liver, is intricately composed of endothelial cells, Kupffer cells, and hepatic stellate cells. Consequently, the homeostasis of the hepatic sinusoidal microenvironment may exert a pivotal influence on the progression and prognosis of NASH. However, the limitations of current NASH animal models have significantly impeded advancements in understanding the disease's pathogenesis and the development of effective therapeutic interventions. In light of these challenges, this review endeavors to delve deeper into the critical role of hepatic sinusoidal microenvironment homeostasis in the pathogenesis of NASH, critically analyze the commonly employed animal models, and comprehensively summarize the most recent and promising developments in drug research and development. It is anticipated that these efforts will collectively expedite the advancement of the field of NASH research and therapeutic innovation.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2+, and SPP1+ macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.

Similarly to conventional steroids, bile acids function as signaling molecules, acting on a family of membrane and nuclear receptors. The best-characterized bile acid-regulated receptors are the farnesoid X receptor, activated by primary bile acids, and the G-protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), which is activated by secondary bile acids, such as lithocholic acid (LCA) and deoxycholic acid. Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity, monocytes/macrophages, and natural killer cells. Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflammation. In recent years, however, it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity. The 3-oxoLCA and isoalloLCA, two LCA derivatives, bind receptors such as the retinoic acid receptor-related orphan receptor gamma t (RORγt) and the vitamin D receptor (VDR) that are expressed only by lymphoid cells, extending the regulatory role of bile acids to T cells, including T-helper 17 cells and type 3 innate lymphoid cells (ILC3). In this novel conceptual framework, bile acids have emerged as one of the main components of the postbiota, the waste array of chemical mediators generated by the intestinal microbiota. Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.

The onset of decompensation in advanced chronic liver disease (ACLD) is a hallmark in natural history, with a poor prognosis and a significantly increased liver-related mortality. Etiological treatments for viral hepatitis or abstinence in cirrhosis due to alcohol abuse have demonstrated that some patients experience partial to complete clinical and analytical improvement, a stage termed "recompensation." Although recompensation is primarily defined clinically based on treatable etiologies, it is still evolving for conditions like metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the need for specific biomarkers in hepatic recompensation, no biomarkers have been thoroughly studied in this context. Biomarkers identified in compensated ACLD (cACLD) following etiological treatment might be explored for recompensation. Although the pathophysiology mechanisms underlying the hepatic recompensation remain unclear, understanding the mechanism involved in cirrhosis decompensation could help identify potential targets for recompensation. This review provides an update on the hepatic recompensation concept, examines the existing data on invasive and non-invasive biomarkers, mainly in cACLD after cure, that could be raised in recompensation, and explores future therapeutic targets for the hepatic recompensation process.

Exposure to fine particulate matter (PM2.5) is associated with increased morbidity and mortality among patients with idiopathic pulmonary fibrosis (IPF). Pathological alterations in IPF typically originate in the subpleural regions of the lungs. However, it was unclear how PM2.5 affected subpleural pulmonary fibrosis. In this study, atmospheric PM2.5 and carbon blacks were utilized as representative particulate matter to investigate these effects. Mouse models and cell models were made to investigate macrophage chemotaxis changes under PM2.5 exposure in vivo and in vitro. The findings indicated that PM2.5 promoted macrophage aggregation in the subpleural region of lung and aggravated bleomycin-induced pulmonary fibrosis in mice. At the same time, we uncovered for the first time that PM2.5 exposure led to an upregulation of midkine, which subsequently enhanced the production of monocyte chemotactic protein-1 (MCP-1) through the cell surface receptor Syndecan 4 (SDC4) in pleural mesothelial cells (PMCs), thereby, inducing macrophage aggregation in subpleural region of lung. Furthermore, our results indicated that PM2.5 and bleomycin facilitated macrophage M1 polarization and the production of profibrotic inflammatory factors, culminating in fibrotic alterations in PMCs, lung fibroblasts, and alveolar epithelial cells. Finally, we demonstrated that inhibition of midkine ameliorated lung function and mitigated pulmonary fibrosis in vivo. In conclusion, our findings elucidated that midkine acted as a novel MCP-1 activator, mediating PM2.5-aggravated experimental pulmonary fibrosis, and suggested that the midkine/SDC4/MCP-1 signal should be a new therapeutic target for the treatment of PM2.5-related IPF.

In recent years, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been proposed to better connect liver disease to metabolic dysfunction, which is the most common chronic liver disease worldwide. MASLD affects more than 30% of individuals globally, and it is diagnosed by the combination of hepatic steatosis and obesity, type 2 diabetes, or two metabolic risk factors. MASLD begins with the buildup of extra fat, often greater than 5%, within the liver, causing liver hepatocytes to become stressed. This can proceed to a more severe form, metabolic dysfunction-associated steatohepatitis (MASH), in 20-30% of people, where inflammation in the liver causes tissue fibrosis, which limits blood flow over time. As fibrosis worsens, MASH may lead to cirrhosis, liver failure, or even liver cancer. While the pathophysiology of MASLD is not fully known, the current "multiple-hits" concept proposes that dietary and lifestyle factors, metabolic factors, and genetic or epigenetic factors contribute to elevated oxidative stress and inflammation, causing liver fibrosis. This review article provides an overview of the pathogenesis of MASLD and evaluates existing therapies as well as pharmacological drugs that are currently being studied in clinical trials for MASLD or MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), a progressive liver disease frequently associated with metabolic disorders such as type 2 diabetes mellitus (T2DM) and obesity, has the potential to progress symptomatically to liver cirrhosis and, in some cases, hepatocellular carcinoma. Hence, an urgent need arises to identify and approve new therapeutic options to improve patient outcomes. Research efforts have focused on either developing dedicated molecules or repurposing drugs already approved for other conditions, such as metabolic diseases. Among the latter, antidiabetic and anti-obesity agents have received the most extensive attention, with pivotal trial results anticipated shortly. However, the primary focus underlying successful regulatory approvals is demonstrating a substantial efficacy in improving liver fibrosis and preventing or ameliorating cirrhosis, the key advanced outcomes within MASLD progression. Besides liver steatosis, the ideal therapeutic candidate should reduce inflammation and fibrosis effectively. Although some agents have shown promise in lowering MASLD-related parameters, evidence of their impact on fibrosis and cirrhosis remains limited. This review aims to evaluate whether antidiabetic and anti-obesity drugs can be safely and effectively used in MASLD-related advanced fibrosis or cirrhosis in patients with T2DM. Our paper discusses the molecules closest to regulatory approval and the expectation that they can address the unmet needs of this increasingly prevalent disease.

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. With the advent of multiple therapeutic targets in late-phase clinical drug development for MASH, there is a knowledge gap to better understand the comparative efficacy of various pharmacological agents. We conducted an updated network meta-analysis to evaluate the relative rank order of the different pharmacological agents for both fibrosis regression and MASH resolution.

We searched PubMed and Embase databases from January 1, 2020 to December 1, 2024, for published randomized controlled trials comparing pharmacological interventions in patients with biopsy-proven MASH. The co-primary endpoints were fibrosis improvement ≥1 stage without MASH worsening and MASH resolution without worsening fibrosis. We conducted surface under the cumulative ranking curve (SUCRA) analysis. A total of 29 randomized controlled trials (n=9324) were included. Pegozafermin, cilofexor + firsocostat, denifanstat, survodutide, obeticholic acid, tirzepatide, resmetirom, and semaglutide were significantly better than placebo in achieving fibrosis regression without worsening MASH. Pegozafermin (SUCRA: 79.92), cilofexor + firsocostat (SUCRA: 71.38), and cilofexor + selonsertib (SUCRA: 69.11) were ranked the most effective interventions. Pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E + pioglitazone, resmetirom, semaglutide, pioglitazone, denifanstat, semaglutide, and lanifibranor were significantly better than placebo in achieving MASH resolution without worsening fibrosis. Pegozafermin (SUCRA: 91.75), survodutide (SUCRA: 90.87), and tirzepatide (SUCRA: 84.70) were ranked the most effective interventions for achieving MASH resolution without worsening fibrosis.

This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design.

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD.

CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its more severe form steatohepatitis (MASH) contribute to rising morbidity and mortality rates. The storage of fat in humans is closely associated with these diseases' progression. Thus, adipose tissue metabolic homeostasis could be key in both the onset and progression of MASH.

We conducted a case-control observational research using a systems biology-based approach to analyse liver, abdominal subcutaneous adipose tissue (SAT), omental visceral adipose tissue (VAT), and blood of n = 100 patients undergoing bariatric surgery (NCT05554224). MASH was diagnosed through histologic assessment. Whole-slide image analysis, lipidomics, proteomics, and transcriptomics were performed on tissue samples. Lipidomics and proteomics profiles were determined on plasma samples.

Liver transcriptomics, proteomics, and lipidomics revealed interconnected pathways associated with inflammation, mitochondrial dysfunction, and lipotoxicity in MASH. Paired adipose tissue biopsies had larger adipocyte areas in both fat depots in MASH. Enrichment analyses of proteomics and lipidomics data confirmed the association of liver lesions with mitochondrial dysfunction in VAT. Plasma lipidomics identified candidates with high diagnostic accuracy (AUC = 0.919, 95% CI 0.840-0.979) for screening MASH.

Mitochondrial dysfunction is also present in VAT in patients with obesity-associated MASH. This may cause a disruption in the metabolic equilibrium of lipid processing and storage, which impacts the liver and accelerates detrimental adaptative responses.

The project leading to these results has received funding from 'la Caixa' Foundation (HR21-00430), and from the Instituto de Salud Carlos III (ISCIII) (PI21/00510) and co-funded by the European Union.

Liver fibrosis develops in response to chronic liver injury and is characterized by a sustained inflammatory response that leads to excessive collagen deposition by myofibroblasts. The fibrogenic response is governed by the release of inflammatory mediators from innate, adaptive, and innate-like lymphoid cells and from nonprofessional immune cells (i.e., epithelial cells, hepatic myofibroblasts, and liver sinusoidal endothelial cells). Upon removal of the underlying cause, liver fibrosis can resolve via activation of specific immune cell subsets. Despite major advances in the understanding of fibrosis pathogenesis, there is still no approved antifibrotic therapy. This review summarizes our current knowledge of the immune cell landscape and the inflammatory mechanisms underlying liver fibrosis progression and regression. We discuss how reprogramming immune cell phenotype, in particular through targeting selective inflammatory pathways or modulating cell-intrinsic metabolism, may be translated into antifibrogenic therapies.

Sepsis-induced acute liver injury (SALI), a manifestation of sepsis multi-organ dysfunction syndrome, is associated with poor prognosis and high mortality. The diversity and plasticity of liver macrophage subpopulations explain their different functional responses in different liver diseases. Kupffer macrophages, liver capsular macrophages, and monocyte-derived macrophages are involved in pathogen recognition and clearance and in the regulation of inflammatory responses, exacerbating the progression of SALI through different pathways of pyroptosis, ferroptosis, and autophagy. Concurrently, they play an important role in maintaining hepatic homeostasis and in the injury and repair processes of SALI. Other macrophages are recruited to diseased tissues under pathological conditions and are polarized into various phenotypes (mainly M1 and M2 types) under the influence of signaling molecules, transcription factors, and metabolic reprogramming, thereby exerting different roles and functions. This review provides an overview of the immune role of macrophages in SALI and discusses the multiple roles of macrophages in liver injury and repair to provide a reference for future studies.

Liver fibrosis is a progressive scarring process primarily caused by chronic inflammation and injury, often closely associated with viral hepatitis, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune liver disease (AILD). Currently, there are very few clinical antifibrotic drugs available, and effective targeted therapy is lacking. Recently, emerging antifibrotic drugs and immunomodulators have shown promising results in animal studies, and some have entered clinical research phases. This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis. Furthermore, since liver fibrosis is a progression or endpoint of many diseases, it is crucial to address the etiological treatment and secondary prevention for liver fibrosis. We will also review the pharmacological treatments available for common hepatitis leading to liver fibrosis.

Fibrosis, an excessive self-repair response, is an age-related pathological process that universally affects various major organs such as the heart, liver, kidney, and lungs. Continuous accumulation of pathological tissue fibrosis destroys structural integrity and causes loss of function, with consequent organ failure and increased mortality. Although some differences exist in the triggering mechanisms and pathophysiologic manifestations of organ-specific fibrosis, they usually share similar cascading responses and features, including chronic inflammatory stimulation, parenchymal cell injury, and macrophage recruitment. Macrophages, due to their high plasticity, can polarize into different phenotypes in response to varied microenvironments and play a crucial role in the development of organ fibrosis. This review examined the relationship between macrophages and the pathogenesis of organ fibrosis. Moreover, it analyzed how fibrosis can be modulated by targeting macrophages, which may become a novel and promising therapeutic strategy for fibrosis.

Macrophages are instrumental in maintaining tissue homeostasis, modulating inflammation, and driving regeneration. The advent of omics techniques has led to the identification of numerous tissue-specific macrophage subtypes, thereby introducing the concept of the "macrophage niche". This paradigm underscores the ability of macrophages to adapt their functions based on environmental cues, such as tissue-specific signals. This adaptability is closely linked to their metabolic states, which are crucial for their function and role in health and disease. Macrophage metabolism is central to their ability to switch between proinflammatory and anti-inflammatory states. In this regard, environmental factors, including the extracellular matrix, cellular interactions, and microbial metabolites, profoundly influence macrophage behavior. Moreover, diet and gut microbiota significantly impact macrophage function, with nutrients and microbial metabolites influencing their activity and contributing to conditions like inflammatory bowel disease. Targeting specific macrophage functions and their metabolic processes is leading to the development of novel treatments for a range of chronic inflammatory conditions. The exploration of macrophage biology enriches our understanding of immune regulation and holds the promise of innovative approaches to managing diseases marked by inflammation and immune dysfunction, offering a frontier for scientific and clinical advancement.

Small cell lung cancer (SCLC) represents an aggressive neuroendocrine (NE) tumor within the pulmonary region, characterized by very poor prognoses. Druggable targets for SCLC remain limited, thereby constraining treatment options available to patients. Immuno-chemotherapy has emerged as a pivotal therapeutic strategy for extensive-stage SCLC (ES-SCLC), yet it fails to confer significant efficacy in cases involving liver metastases (LMs) originating from SCLC. Therefore, our attention is directed towards the challenging subset of SCLC patients with LMs. Disease progression of LM-SCLC patients is affected by various factors in the tumor microenvironment (TME), including immune cells, blood vessels, inflammatory mediators, metabolites, and NE substances. Beyond standard immuno-chemotherapy, ongoing efforts to manage LMs in SCLC encompass anti-angiogenic therapy, radiotherapy, microwave ablation (MWA) / radiofrequency ablation (RFA), trans-arterial chemoembolization (TACE), and systemic therapies in conjunction with local interventions. Prospective experimental and clinical investigations into SCLC should prioritize precise and individualized approaches to enhance the prognosis across distinct patient cohorts.

Macrophages, the predominant immune cells in the liver, are essential for maintaining hepatic homeostasis and responding to liver injury caused by external stressors. The hepatic macrophage population is highly heterogeneous and plastic, mainly comprised of hepatic resident kuffer cells (KCs), monocyte-derived macrophages (MoMφs), lipid-associated macrophages (LAMs), and liver capsular macrophages (LCMs). KCs, a population of resident macrophages, are localized in the liver and can self-renew through in situ proliferation. However, MoMφs in the liver are recruited from the periphery circulation. LAMs are a self-renewing subgroup of liver macrophages near the bile duct. While LCMs are located in the liver capsule and derived from peripheral monocytes. LAMs and LCMs are also involved in liver damage induced by various factors. Hepatic macrophages exhibit distinct phenotypes and functions depending on the specific microenvironment in the liver. KCs are critical for initiating inflammatory responses after sensing tissue damage, while the MoMφs infiltrated in the liver are implicated in both the progression and resolution of chronic hepatic inflammation and fibrosis. The regulatory function of liver macrophages in hepatic fibrosis has attracted significant interest in current research. Numerous literatures have documented that the MoMφs in the liver have a dual impact on the progression and resolution of liver fibrosis. The MoMφs in the liver can be categorized into two subtypes based on their Ly-6C expression level: inflammatory macrophages with high Ly-6C expression (referred to as Ly-6Chi subgroup macrophages) and reparative macrophages with low Ly-6C expression (referred to as Ly-6Clo subgroup macrophages). Ly-6Chi subgroup macrophages are conducive to the occurrence and progression of liver fibrosis, while Ly-6Clo subgroup macrophages are associated with the degradation of extracellular matrix (ECM) and regression of liver fibrosis. Given this, liver macrophages play a pivotal role in the occurrence, progression, and regression of liver fibrosis. Based on these studies, treatment therapies targeting liver macrophages are also being studied gradually. This review aims to summarize researches on the composition and origin of liver macrophages, the macrophage heterogeneity in the progression and regression of liver fibrosis, and anti-fibrosis therapeutic strategies targeting macrophages in the liver.

The global incidence of nonalcoholic fatty liver disease (NAFLD) is escalating considerably. NAFLD covers a range of liver conditions from simple steatosis to the more severe form known as nonalcoholic steatohepatitis, which involves chronic liver inflammation and the transformation of hepatic stellate cells into myofibroblasts that generate excess extracellular matrix, leading to fibrosis. Hepatocyte ballooning is a key catalyst for fibrosis progression, potentially advancing to cirrhosis and its decompensated state. Fibrosis is a critical prognostic factor for outcomes in patients with NAFLD; therefore, those with substantial fibrosis require timely intervention. Although liver biopsy is the most reliable method for fibrosis detection, it is associated with certain risks and limitations, particularly in routine screening. Consequently, various noninvasive diagnostic techniques have been introduced. This review examines the increasing prevalence of NAFLD, evaluates the noninvasive diagnostic techniques for fibrosis, and assesses their efficacy in staging the disease. In addition, it critically appraises current and emerging antifibrotic therapies, focusing on their mechanisms, efficacy, and potential in reversing fibrosis. This review underscores the urgent need for effective therapeutic strategies, given the dire consequences of advanced fibrosis.

Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.

Nonalcoholic fatty liver disease (NAFLD), more appropriately known as metabolic (dysfunction) associated fatty liver disease (MAFLD), a prevalent condition in type 2 diabetes mellitus (T2DM) patients, is a complex condition involving hepatic lipid accumulation, inflammation, and liver fibrosis. The gut-liver axis is closely linked to metabolic dysfunction, insulin resistance, inflammation, and oxidative stress that are leading to the cooccurrence of MAFLD and T2DM cardiovascular diseases (CVDs). The purpose of this review is to raise awareness about the role of the gut-liver axis in the progression of MAFLD, T2DM and CVDs with a critical analysis of available treatment options for T2DM and MAFLD and their impact on cardiovascular health. This study analysed over 100 articles on this topic, using online searches and predefined keywords, to understand and summarise published research. Numerous studies have shown a strong correlation between gut dysfunction, particularly the gut microbiota and its metabolites, and the occurrence and progression of MAFLD and type 2 diabetes mellitus (T2DM). Herein, this article also examines the impact of the gut-liver axis on MAFLD, T2DM, and related complications, focusing on the role of gut microbiota dysbiosis in insulin resistance, T2DM and obesity-related cardiovascular complications. The study suggests potential treatment targets for MAFLD linked to T2DM, focusing on cardiovascular outcomes and the molecular mechanism of the gut-liver axis, as gut microbiota dysbiosis contributes to obesity-related metabolic abnormalities.

Metabolic dysfunction-associated steatotic liver disease (MASLD), represents a growing health concern due to its strong association with metabolic syndrome, obesity, and type 2 diabetes mellitus (T2DM). This condition, characterized by excessive fat accumulation in the liver not attributed to alcohol consumption, has emerged as a leading cause of chronic liver disease globally. MASLD significantly elevates the risk of major adverse cardiovascular events (MACE) through mechanisms like increased oxidative stress, insulin resistance, and chronic inflammation, all of which contribute to the development of atherosclerosis and endothelial dysfunction. Effective management of MASLD is crucial not only for liver health but also for cardiovascular disease (CVD) prevention. Lifestyle modifications, particularly weight loss achieved through dietary changes and increased physical activity, are the cornerstone of MASLD treatment. Additionally, pharmacological interventions, especially antihyperglycemic agents, play a pivotal role in treating MASLD in patients with T2DM. Novel therapeutic agents targeting various pathways of metabolic and liver dysfunction are under investigation, offering hope for more effective management strategies. This review explores the interconnectedness of MASLD and CVD, highlighting current and emerging therapeutic approaches.

Although multiple approaches have been suggested, treating mild-to-severe fibrosis in the context of metabolic dysfunction associated with liver disease (MASLD) remains a challenging area in drug discovery. Pathogenesis of liver fibrosis is multifactorial, and pathogenic mechanisms are deeply intertwined; thus, it is well accepted that future treatment requires the development of multitarget modulators. Harnessing the 3,4,5-trisubstituted isoxazole scaffold, previously described as a key moiety in Farnesoid X receptor (FXR) agonism, herein we report the discovery of a novel class of hybrid molecules endowed with dual activity toward FXR and the leukemia inhibitory factor receptor (LIFR). Up to 27 new derivatives were designed and synthesized. The pharmacological characterization of this series resulted in the identification of 3a as a potent FXR agonist and LIFR antagonist with excellent ADME properties. In vitro and in vivo characterization identified compound 3a as the first-in-class hybrid LIFR inhibitor and FXR agonist that protects against the development of acute liver fibrosis and inflammation.

Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630's potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH.

SNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers.

SNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis.

SNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH.

ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566.

Metabolic dysfunction-associated steatohepatitis (MASH), a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), poses a significant threat to global health. Despite extensive research efforts over the past decade, only one drug has received market approval under accelerated pathways. In this review, we summarise the pathogenesis of MASH and present a comprehensive overview of recent advances in phase 2-3 clinical trials targeting MASH. These trials have highlighted considerable challenges, including low response rates to drugs, limitations of current surrogate histological endpoints, and inadequacies in the design of MASH clinical trials, all of which hinder the progress of MASH pharmacotherapy. We also explored the potential of non-invasive tests to enhance clinical trial design. Furthermore, given the strong association between MASLD and cardiometabolic disorders, we advocate for an integrated approach to disease management to improve overall patient outcomes. Continued investigation into the mechanisms and pharmacology of combination therapies may offer valuable insights for developing innovative MASH treatments.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH.

Hepatic fibrosis (HF) is an essential stage in the progression of different chronic liver conditions to cirrhosis and even hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) plays a crucial role in the progression of HF. IFN- γ/Smad7 pathway can inhibit HSCs activation, while TGF-β1/CUGBP1 pathway can inhibit IFN-γ/Smad7 pathway transduction and promote HSCs activation. Thus, inhibiting the TGF-β1/CUGBP1 pathway and activating the IFN-γ/Smad7 pathway reverses HSCs activation and inhibits HF. Jiawei Taohe Chengqi Decoction (JTCD) was derived from the Taohe Chengqi Tang in the ancient Chinese medical text titled "Treatise on Febrile Diseases". We found several anti-HF components in JTCD including ginsenoside Rb1 and others, but the specific mechanism of anti-HF in JTCD is not clear.

To elucidate the specific mechanism by which JTCD reverses HF by inhibiting the activation of HSCs, and to establish a scientific foundation for treating HF with Traditional Chinese medicine (TCM).

We constructed a CCl4-induced mice HF model in vivo and activated human hepatic stellate cell line (LX-2) with TGF-β1 in vitro, after which they were treated with JTCD and the corresponding inhibitors. We examined the expression of pivotal molecules in the two pathways mentioned above by immunofluorescence staining, Western blotting and RT-PCR.

JTCD attenuated liver injury and reduced serum ALT and AST levels in mice. In addition, JTCD attenuated CCl4-induced HF by decreasing the expression of α-SMA, COL1A1 and other markers of HSCs activation in mice liver tissue. Moreover, JTCD effectively suppressed the levels of TGF-β1, p-Smad3, p-p38MAPK, p-ATF2, and CUGBP1 in vivo and in vitro and upregulated the levels of IFN-γ, p-STAT1, and Smad7. Mechanically, after using the inhibitors of both pathways in vitro, we found that JTCD inhibited the activation of HSCs by restoring the balance of the TGF-β1/CUGBP1 and IFN-γ/Smad7 pathways.

We demonstrated that JTCD inhibited HSCs activation and reversed HF by inhibiting the TGF-β1/CUGBP1 signalling pathway and upregulating the IFN-γ/Smad7 signalling pathway. Moreover, we have identified specific links where JTCD interferes with both pathways to inhibit HSCs activation. JTCD is an effective candidate for the clinical treatment of HF.

On March 14, 2024, after more than 25 years of intense research and a long series of failures, the Food and Drug Administration approved resmetirom as first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis (now Metabolic-Associated Steatotic Liver Disease - MASLD). The present review covers this difficult process, finally providing a drug to complement lifestyle intervention, that has long been the sole approved therapeutic intervention. However, the availability of a drug shown to reduce disease progression in advanced stages of diseases opens a series of questions that deserve even more intense research. How to continue ongoing trials? How to generate an appropriate use of resmetirom in the community, limiting treatment according to predefined criteria and according to individual risk assessment? How to guarantee that both hepatic and non-hepatic comorbidities are appropriately targeted? How to define cost-effective strategies that might prevent the generation of unacceptable differences within the population, given the high costs of novel drugs and the extremely high numbers of candidates to treatment? Only a close surveillance of drug use in the real world, generated by insurance databases and national healthcare system registries, might provide adequate answers to these compelling questions.

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.

Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses metabolic dysfunction-associated fatty liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), with MASH posing a risk of progression to cirrhosis and hepatocellular carcinoma (HCC). The global prevalence of MASLD is estimated at approximately a quarter of the population, with significant healthcare costs and implications for liver transplantation. The pathogenesis of MASLD involves intrahepatic liver cells, extrahepatic components, and immunological aspects, particularly the involvement of macrophages. Hepatic macrophages are a crucial cellular component of the liver and play important roles in liver function, contributing significantly to tissue homeostasis and swift responses during pathophysiological conditions. Recent advancements in technology have revealed the remarkable heterogeneity and plasticity of hepatic macrophage populations and their activation states in MASLD, challenging traditional classification methods like the M1/M2 paradigm and highlighting the coexistence of harmful and beneficial macrophage phenotypes that are dynamically regulated during MASLD progression. This complexity underscores the importance of considering macrophage heterogeneity in therapeutic targeting strategies, including their distinct ontogeny and functional phenotypes. This review provides an overview of macrophage involvement in MASLD progression, combining traditional paradigms with recent insights from single-cell analysis and spatial dynamics. It also addresses unresolved questions and challenges in this area.

To investigate type III collagen (COL III) turnover in participants from the CANVAS Program biomarker substudy.

Biomarkers of COL III formation (PRO-C3) and COL III degradation fragments (C3M and CTX-III) were assessed in baseline and year 3 plasma from patients enrolled in CANVAS, investigating the effect of canagliflozin in participants with type 2 diabetes. The clinical outcomes investigated in this study were hospitalization for heart failure, cardiovascular death and all-cause mortality.

Higher levels of PRO-C3 and C3M at baseline were associated with an increased incidence of all investigated outcomes, whereas levels of CTX-III at baseline were not associated with any of the investigated outcomes. Levels of PRO-C3 decreased and levels of CTX-III increased following canagliflozin treatment. An increase from baseline to year 3 in PRO-C3 in the placebo arm was associated with an increased incidence of cardiovascular outcomes, and in all participants was associated with an increased risk of all-cause mortality.

The changes in PRO-C3 and CTX-III reflect a shift in the dynamics of COL3 turnover following treatment with canagliflozin. These biomarkers are promising pharmacodynamic tools that can be used to monitor the impact of canagliflozin treatment and possibly other sodium-glucose co-transporter-2 inhibitors on tissue remodelling in future interventional trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Cenicriviroc (CVC) is a CCR2/CCR5 antagonist that has been shown to be effective in the treatment of inflammatory and fibrotic diseases. Our study evaluated its efficacy in colitis.

Mouse models of DSS-induced acute and chronic colitis were established. The efficacy of CVC in colitis was assessed by disease activity index (DAI) scores, histological assessment of inflammation and fibrosis, and expression assays of key molecules. In in vitro experiments, HT29 cell line was exposed to TNFα to study inflammatory signaling in intestinal epithelial cells. CCD-18Co colonic myofibroblasts and human primary colonic fibroblasts were activated by TGFβ1 to mimic fibroblast activation.

In HT29 cells, CVC significantly reduced mRNA expression of CCL5 (P < 0.01) but had no effect on CCL2. Furthermore, CVC reduced downstream CX3CL1 (P < 0.01) and TNFα (P < 0.05) expression, thereby inhibiting inflammatory progression. In acute colitis mice, CVC significantly reduced DAI scores and serum TNFα levels (P < 0.05) and attenuated colonic inflammation as shown by HE staining. Meanwhile, CVC had no adverse effects on the liver, heart, and kidney of mice. On the other hand, in cellular models of chronic colitis, CVC decreased the expression of fibrosis markers, including FN, CTGF, α-SMA, and MMP9, and inhibited TGFβ1-induced fibrotic activation (P < 0.01). In addition, CVC attenuated colonic fibrosis in chronic colitis mice. Moreover, CVC significantly promoted autophagy, which contributed to its regulation of inflammation.

CVC significantly inhibited inflammation through CCL5/CCR5 signaling without damaging vital organs and suppressed fibrotic activation in chronic colitis, suggesting its great potential to relieve colonic inflammation and fibrosis.