Chaperone-mediated autophagy (CMA) is a selective type of autophagy targeting protein degradation and maintains high activity in many malignancies. Inhibition of the combination of HSC70 and LAMP2A can potently block CMA. At present, knockdown of LAMP2A remains the most specific method for inhibiting CMA and chemical inhibitors against CMA have not yet been discovered.

Levels of CMA in non-small cell lung cancer (NSCLC) tissue samples were confirmed by tyramide signal amplification dual immunofluorescence assay. High-content screening was performed based on CMA activity, to identify potential inhibitors of CMA. Inhibitor targets were determined by drug affinity responsive target stability-mass spectrum and confirmed by protein mass spectrometry. CMA was inhibited and activated to elucidate the molecular mechanism of the CMA inhibitor.

Suppression of interactions between HSC70 and LAMP2A blocked CMA in NSCLC, restraining tumour growth. Polyphyllin D (PPD) was identified as a targeted CMA small-molecule inhibitor through disrupting HSC70-LAMP2A interactions. The binding sites for PPD were E129 and T278 at the nucleotide-binding domain of HSC70 and C-terminal of LAMP2A, respectively. PPD accelerated unfolded protein generation to induce reactive oxygen species (ROS) accumulation by inhibiting HSC70-LAMP2A-eIF2α signalling axis. Also, PPD prevented regulatory compensation of macroautophagy induced by CMA inhibition via blocking the STX17-SNAP29-VAMP8 signalling axis.

PPD is a targeted CMA inhibitor that blocked both HSC70-LAMP2A interactions and LAMP2A homo-multimerization. CMA suppression without increasing the regulatory compensation from macroautophagy is a good strategy for NSCLC therapy.

This article is part of a themed issue Natural Products and Cancer: From Drug Discovery to Prevention and Therapy. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.10/issuetoc.

Therapy resistance is a major barrier to achieving a cure in cancer patients, often resulting in relapses and mortality. Heat shock proteins (HSPs) are a group of evolutionarily conserved proteins that play a prominent role in the progression of cancer and drug resistance. HSP synthesis is upregulated in cancer cells, facilitating adaptation to various tumor microenvironment (TME) stressors, including nutrient deprivation, exposure to DNA-damaging agents, hypoxia, and immune responses. In this review, we present background information about HSP-mediated cancer therapy resistance. Within this context, we emphasize recent progress in the understanding of HSP machinery, exploring the therapeutic potential of HSPs in cancer treatment.

We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate, and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain, and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K, and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system, and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and proferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide, and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression, and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.

In drug development, systematically characterizing a compound's mechanism of action (MoA), including its direct targets and effector proteins, is crucial yet challenging. Network-based approaches, unlike those focused solely on direct targets, effectively detect a wide range of cellular responses elicited by compounds. This study applied protein covariation network analysis, leveraging quantitative, morphological, and localization features from immunostained microscopic images, to elucidate the MoA of AX-53802, a novel ferroptosis inducer. From the candidate targets extracted through network analysis, GPX4 was verified as the direct target by validation experiments. Additionally, aggregates involving GPX4, TfR1, and F-actin were observed alongside iron reduction, suggesting a ferroptosis defense mechanism. Furthermore, combination therapies targeting GPX4 and FAK/Src were found to enhance cancer cell death, and MDM2, ezrin, and cortactin were identified as potential ferroptosis inhibitor targets. These findings highlight the effectiveness of network-based approaches in uncovering a compound's MoA and developing combination therapies for cancer.

Autophagy is a lysosome-dependent degradation pathway for recycling intracellular materials and removing damaged organelles, and it is usually considered a prosurvival process in response to stress stimuli. However, increasing evidence suggests that autophagy can also drive cell death in a context-dependent manner. The bulk degradation of cell contents and the accumulation of autophagosomes are recognized as the mechanisms of cell death induced by autophagy alone. However, autophagy can also drive other forms of regulated cell death (RCD) whose mechanisms are not related to excessive autophagic vacuolization. Notably, few reviews address studies on the transformation from autophagy to RCD, and the underlying molecular mechanisms are still vague.

This review aims to summarize the existing studies on autophagy-mediated RCD, to elucidate the mechanism by which autophagy initiates RCD, and to comprehensively understand the role of autophagy in determining cell fate.

This review highlights the prodeath effect of autophagy, which is distinct from the generally perceived cytoprotective role, and its mechanisms are mainly associated with the selective degradation of proteins or organelles essential for cell survival and the direct involvement of the autophagy machinery in cell death. Additionally, this review highlights the need for better manipulation of autophagy activation or inhibition in different pathological contexts, depending on clinical purpose.

Ferroptosis, a regulated iron-dependent cell death pathway driven by lipid peroxidation and mitochondrial dysfunction, has emerged as a critical player in diseases characterized by dysregulated iron metabolism and redox imbalance. In recent years, its therapeutic potential has garnered significant attention in head and neck squamous cell carcinoma (HNSCC), a malignancy notorious for its high incidence, frequent recurrence, and poor prognosis. This review systematically delineates the molecular underpinnings of ferroptosis in HNSCC pathogenesis and therapy, focusing on four interconnected axes: (1) iron homeostasis disruption, exemplified by dysregulation of the iron efflux channel ferroportin (FPN); (2) lipid peroxidation dynamics, mediated through key regulators such as SLC7A11; (3) mitochondrial remodeling, including structural and functional alterations during ferroptosis execution; and (4) critical signaling cascades, notably the PI3K-AKT-mTOR pathway, which orchestrates cellular survival and death decisions. Therapeutic exploration has identified ferroptosis inducers (e.g., erastin) as promising agents to disrupt redox equilibrium in HNSCC cells, while pharmacological inhibitors offer potential for mitigating off-target toxicity. Notably, combination strategies integrating ferroptosis modulation with conventional therapies or other programmed cell death mechanisms demonstrate synergistic efficacy, highlighting a paradigm shift in precision oncology. This study aims to provide a mechanistic framework for ferroptosis in HNSCC, bridging preclinical insights with translational opportunities. By elucidating context-dependent regulatory networks and optimizing therapeutic targeting, we propose novel strategies to overcome treatment resistance, ultimately improving clinical outcomes and quality of life for HNSCC patients.

Myocardial ischemia-reperfusion (I/R) injury is a multifaceted process observed in patients with coronary artery disease when blood flow is restored to the heart tissue following ischemia-induced damage. Cardiomyocyte cell death, particularly through apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, is pivotal in myocardial I/R injury. Preventing cell death during the process of I/R is vital for improving ischemic cardiomyopathy. These multiple forms of cell death can occur simultaneously, interact with each other, and contribute to the complexity of myocardial I/R injury. In this review, we aim to provide a comprehensive summary of the key molecular mechanisms and regulatory patterns involved in these five types of cell death in myocardial I/R injury. We will also discuss the crosstalk and intricate interactions among these mechanisms, highlighting the interplay between different types of cell death. Furthermore, we will explore specific molecules or targets that participate in different cell death pathways and elucidate their mechanisms of action. It is important to note that manipulating the molecules or targets involved in distinct cell death processes may have a significant impact on reducing myocardial I/R injury. By enhancing researchers' understanding of the mechanisms and interactions among different types of cell death in myocardial I/R injury, this review aims to pave the way for the development of novel interventions for cardio-protection in patients affected by myocardial I/R injury.

The occurrence of necrosis during Mycobacterium bovis (M. bovis) infection is regarded as harmful to the host because it promotes the spread of M. bovis. Ferroptosis is a controlled type of cell death that occurs when there is an excessive buildup of both free iron and harmful lipid peroxides. Here, we demonstrate that the mammalian cell entry (Mce) 4 family protein Mb3523c triggers ferroptosis to promote M. bovis pathogenicity and dissemination. Mechanistically, Mb3523c, through its Y237 and G241 site, interacts with host HSP90 protein to stabilize the LAMP2A on the lysosome to promote the chaperone-mediated autophagy (CMA) pathway. Then, GPX4 is delivered to lysosomes for destruction via the CMA pathway, eventually inducing ferroptosis to promote M. bovis transmission. In summary, our findings offer novel insights into the molecular mechanisms of pathogen-induced ferroptosis, demonstrating that targeting the GPX4-dependent ferroptosis through blocking the M. bovis Mb3523c-host HSP90 interface represents a potential therapeutic strategy for tuberculosis (TB).Abbreviations: CFU: colony-forming units; CMA: chaperone-mediated autophagy; Co-IP: co-immunoprecipitation; Fer-1: ferrostatin-1; GPX4: glutathione peroxidase 4; HSP90: heat shock protein 90; LDH: lactate dehydrogenase; Mce: mammalian cell entry; MOI: multiplicity of infection; Nec-1: necrostatin-1; PI: propidium iodide; RCD: regulated cell death.

Dysfunction of keratinocytes affects diabetic wound healing, but underlying mechanisms have not been understood. This study examines crotonylation's role in ferroptosis and autophagy in keratinocytes, particularly regarding ACSL4, using STZ-induced diabetic rats and high glucose-exposed keratinocytes to assess these processes. The ACSL4 knockdown was achieved using adenovirus in wounds to examine the impact of ferroptosis modulation on healing diabetic wounds. MB-3 was utilized to block the H3K27 crotonylation (H3K27cr) in order to clarify the regulatory function of crotonylation in both autophagy and ferroptosis. In STZ-induced diabetic skin and high glucose-exposed keratinocytes, ferroptosis mediated by ACSL4 and suppression of autophagic flux were demonstrated. Moreover, the downregulation of ACSL4 triggered ferroptosis in adjacent wounds of diabetic rats and improved wound healing. The degradation of ACSL4 may be observed via the autophagy-lysosome pathway in keratinocytes. Downregulation of SQSTM1 in diabetic keratinocytes leads to autophagy inhibition and modulates the protein level of ACSL4. Mechanistically, total crotonylation levels and H3K27cr were remarkably elevated in the skin and keratinocytes of diabetic rats; blocking high glucose-induced H3K27cr with MB-3 can enhance SQSTM1 transcription and expression while promoting autophagy and reducing ACSL4-induced ferroptosis in keratinocytes. Therefore, H3K27cr influences autophagy by adjusting SQSTM1 to facilitate ACSL4-triggered ferroptosis in diabetic keratinocytes. This study clarifies the relationships between acylation modifications, autophagy, and ferroptosis, while also offering mechanistic insights and potential therapeutic targets for issues associated with diabetic wound healing.

Intervertebral disc degeneration (IVDD) is one of the most common musculoskeletal disorders in middle-aged and elderly people, and lower back pain (LBP) is the main clinical symptom [1, 2], which often causes significant pain and great economic burden to patients [3]. The current molecular mechanisms of IVDD include extracellular matrix degradation, cellular pyroptosis, apoptosis, necrotic apoptosis, senescence, and the newly discovered ferroptosis [4, 5], among which ferroptosis, as a new hot spot of research, has a non-negligible role in IVDD. Ferroptosis is an iron-dependent cell death caused by lipid peroxide accumulation [6]. Its main mechanism is cell death caused by lipid peroxidation by oxygen radicals due to iron overload and inhibition of pathways such as SLC7A11-GSH-GPX4. Currently, more and more studies have found a close relationship between IVDD and ferroptosis [7]. In the process of ferroptosis, the most important factors are abnormal iron metabolism, increased ROS, lipid peroxidation, and abnormal proteins such as GSH, GPX4, and system XC-. Our group has previously elucidated the pathogenesis of IVDD in terms of extracellular matrix degradation, myeloid cell senescence and pyroptosis, apoptosis, and inflammatory immunity. Therefore, this time, we will use ferroptosis as an entry point to discover the new mechanism of IVDD and provide guidance for clinical treatment.

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous obstructive diseases characterized by airflow limitations and are recognized as significant contributors to fatality all over the globe. Asthma accounts for about 4, 55,000 deaths, and COPD is the 3rd leading contributor of mortality worldwide. The pathogenesis of these two obstructive disorders is complex and involves numerous mechanistic pathways, including inflammation-mediated and non-inflammation-mediated pathways. Among all the pathological categorizations, programmed cell deaths (PCDs) play a dominating role in the progression of these obstructive diseases. The two major PCDs that are involved in structural and functional remodeling in the progression of asthma and COPD are Pyroptosis and Ferroptosis. Pyroptosis is a PCD mechanism mediated by the activation of the Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, leading to the maturation and release of Interleukin-1β and Interleukin-18, whereas ferroptosis is a lipid peroxidation-associated cell death. In this review, the major molecular pathways contributing to these multifaceted cell deaths have been discussed, and crosstalk among them regarding the pathogenesis of asthma and COPD has been highlighted. Further, the possible therapeutic approaches that can be utilized to mitigate both cell deaths at once have also been illustrated.

Atherosclerosis (AS) is a serious disease that poses a significant threat to the global population. In this review, we analyze the development of AS from multiple perspectives, aiming to elucidate its molecular mechanisms. We also focus on imaging techniques and therapeutic approaches, highlighting the crucial role of nanomaterials in both imaging and therapy for AS. By leveraging their compatibility and targeting capabilities, nanomaterials can be integrated with traditional medical imaging and therapeutic agents to achieve targeted drug delivery, controlled release, and precise localization and imaging of atherosclerotic plaques.

Ferroptosis is an iron-dependent nonapoptotic regulated cell death modality characterized by lethal levels of lipid peroxide accumulation and disrupted antioxidant systems. An increasing number of studies have revealed correlations between ferroptosis and the pathophysiology and treatment of cancer. Given the intricate involvement of mitochondria in ferroptosis, as suggested by previous studies, here, we review advances in understanding the roles of mitochondrial quality control and mitochondrial metabolism (including the roles of the TCA cycle, reactive oxygen species, iron metabolism, and lipid metabolism) in cancer-related ferroptosis and outline the molecular mechanism and clinical translation of mitochondria-related ferroptosis in cancer treatment. with the aim of promoting the precise utilization and prevention of ferroptosis in cancer therapeutics.

The phenomenon of cell death has garnered significant scientific attention in recent years, emerging as a pivotal area of research. Recently, novel modalities of cellular death and the intricate interplay between them have been unveiled, offering insights into the pathogenesis of various diseases. This comprehensive review delves into the intricate molecular mechanisms, inducers, and inhibitors of the underlying prevalent forms of cell death, including apoptosis, autophagy, ferroptosis, necroptosis, mitophagy, and pyroptosis. Moreover, it elucidates the crosstalk and interconnection among the key pathways or molecular entities associated with these pathways, thereby paving the way for the identification of novel therapeutic targets, disease management strategies, and drug repurposing.

Ischemic stroke is a leading cause of disability and death worldwide, largely due to its increasing incidence associated with an aging population. This condition results from arterial obstruction, significantly affecting patients' quality of life and imposing a substantial economic burden on healthcare systems. While current treatments primarily focus on the rapid restoration of blood flow through thrombolytic therapy or surgical interventions, a limited understanding of neuronal injury mechanisms hampers the development of more effective treatments.This article explores the interplay among various cell death pathways-necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis-in the context of ischemic stroke to identify novel therapeutic targets. Each mode of cell death displays unique characteristics and roles post-stroke, and the activation of these pathways may vary across different animal models, complicating the translation of therapeutic strategies to clinical settings. Notably, the interaction between apoptosis and necroptosis is highlighted; inhibiting apoptosis might heighten the risk of necroptosis. Therefore, a balanced regulation of these pathways could promote enhanced neuronal survival.Additionally, we introduce PANoptosis, a form of cell death that encompasses pyroptosis, apoptosis, and necroptosis, emphasizing the complexity and potential therapeutic implications of these interactions. In summary, understanding the relationships among these cell death mechanisms in ischemic stroke is vital for developing new neuroprotective agents. Future research should aim for combinatorial interventions targeting multiple pathways to optimize treatment strategies and improve patient outcomes.

Autophagy refers to the proteolytic degradation of cytoplasmic components by lysosomes, and includes three defined types: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the regulatory pathways of macroautophagy are well defined, how CMA is accurately regulated remains less understood. In recent years, emerging evidence has suggested that chaperone-mediated autophagy is regulated by multiple mechanisms at nucleic acid and protein levels. In this review, we summarized recent progress on multiple regulatory mechanisms and functions concerning CMA, as well as novel treatments targeting specific regulation sites.

Programmed cell death is a type of autonomic and orderly cell death mode controlled by genes that maintain homeostasis and growth. Tumor is a typical manifestation of an imbalance in environmental homeostasis in the human body. Currently, several tumor treatments are designed to trigger the death of tumor cells. Nasopharyngeal carcinoma is one of the most common malignant tumors in China. It displays obvious regional and ethnic differences in its incidence, being typically high in the south and low in the north of China. Nasopharyngeal carcinoma is currently considered to be a polygenic inherited disease and is often mediated by the interaction between multiple genes or between genes and the environment. Apoptosis has long been considered the key to tumor treatment, while other cell death pathways have often been overlooked. The current study provides an overview of the relationship among apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and nasopharyngeal carcinoma, and the regulatory pathways of nasopharyngeal carcinoma based on five cell death modes were synthesized from the view of molecule. We hope this review will help explore additional, novel programmed cell death targets for the treatment of nasopharyngeal carcinoma and thus promote in-depth research.

Evidence suggests that the progression of acute kidney injury (AKI) is driven by tubular epithelial cell (TEC) injury. However, the role of ferroptosis during the regulatory process remains unclear. Fifty-three patients with AKI were included to examine the expressions of Rab7, glutathione peroxidase 4 (GPX4), and Hif-1α by immunohistochemistry. The relationship between these expressions and serum creatinine (Scr) and blood urea nitrogen (BUN) levels was analyzed. After inducing AKI and ferroptosis through bilateral renal artery ischemia-reperfusion injury (I/R) in vivo and hypoxia in vitro, we examined the expression of Rab7. The injury and ferroptosis were observed following the administration of erastin or ferrostatin-1 (Fer-1), as well as the downregulation of Rab7. In addition, we investigated the degradation of GPX4 and chaperone-mediated autophagy (CMA). Finally, we assessed the injury and ferroptosis after the combination of RAS-selective lethal 3 (RSL3) and downregulation of Rab7. GPX4 exhibited an inverse correlation with Hif-1α, Scr, BUN, and Rab7. Conversely, Rab7 was positively correlated with Scr and BUN. Both in vivo and in vitro models resulted in elevated levels of ferroptosis and Rab7. Erastin exacerbated ferroptosis and injury, but this effect was mitigated by Fer-1. Downregulation of Rab7 reversed the increased ferroptosis and injury. Hypoxia enhanced lysosomal transport and degradation of GPX4 through activation of CMA. Furthermore, the reversal of these effects was observed upon the downregulation of Rab7. However, the results obtained from Rab7 downregulation were subsequently reversed by RSL3. Ferroptosis is important in TEC injury during AKI and Rab7 promotes tubular ferroptosis by facilitating CMA-mediated degradation of GPX4.NEW & NOTEWORTHY To explore the mechanism underlying ferroptosis in I/R-induced renal injury and to confirm the effect of Rab7, we first evaluated ferroptosis in renal biopsy samples, and then examined Rab7 expression and renal tubular injury during AKI in vivo and in vitro. Finally, we performed in vitro experiments to investigate the specific role of Rab7 in the regulation of ferroptosis and showed that the regulatory mechanism was related to CMA-mediated GPX4 degradation in renal TECs.

Ferroptosis is a form of programmed cell death that is distinct from apoptosis. The mechanism involves redox‑active metallic iron and is characterized by an abnormal increase in iron‑dependent lipid reactive oxygen species, which results in high levels of membrane lipid peroxides. The relationship between ferroptosis and gynaecological tumours is complex. Ferroptosis can regulate tumour proliferation, metastasis and chemotherapy resistance, and targeting ferroptosis is a promising antitumour approach. Ferroptosis interacts with mechanisms related to tumorigenesis and development, such as macrophage polarization, the neutrophil trap network, mitochondrial autophagy and cuproptosis. The present review examines recent information on the interaction between the molecular mechanism of ferroptosis and other tumour‑related mechanisms, as well as the involvement of ferroptosis in gynaecological tumours, to identify implications for gynaecological cancer therapy.

The Daqinjiao decoction (DQJT), a classical prescription, has been utilized for millennia in stroke management, yet its underlying mechanisms remained obscure.

The aim of this study was to elucidate the mechanisms through which DQJT mitigates cerebral ischemia/reperfusion injury (CI/RI).

The quantification of DQJT's primary components were performed by HPLC. Pharmacological assessments were then conducted to ascertain DQJT's efficacy in a Middle Cerebral Artery Occlusion/Reperfusion (MCAO/R) model. Following this, untargeted metabolomics, lipidomics and network pharmacology analyses were undertaken to unveil potential mechanisms, which were subsequently validated. UPLC-Q-TOF/MS was utilized to detect DQJT-derived chemicals in brain tissue, and molecular docking techniques were employed to investigate the bioactive compounds.

DQJT treatment reduced brain damage induced by MCAO/R, as evidenced by decreased infarct sizes, enhanced behavioral function scores, and diminished neuronal damages. Untargeted metabolomics and lipidomics revealed that DQJT improved metabolism of unsaturated fatty acids. According to network pharmacology, lipid metabolism, cAMP signaling pathway and toll-like receptor signaling pathway pathways were notably affected, with HSP90AA1, TLR4, and PKA identified as potential targets of DQJT. Immunofluorescence and Western blot analyses further demonstrated that DQJT counteracted necroptosis and ferroptosis by inhibiting the HSP90AA1 and TLR4 pathways and enhancing the PKA pathway. Molecular docking results supported that the possible pharmacodynamic substances of DQJT in protecting against CI/RI.

This research established that DQJT attenuates brain injury induced by MCAO/R through the modulation of necroptosis and ferroptosis via pathways including HSP90AA1, TLR4, and PKA. It shed light on the potential mechanisms and effective constituents of DQJT in stroke treatment, paving the way for further exploration of this ancient formula.

The structural and functional integrity of the retinal pigment epithelium (RPE) plays a key role in the normal functioning of the visual system. RPE cells are characterized by an efficient system of photoreceptor outer segment phagocytosis, high metabolic activity, and risk of oxidative damage. RPE dysfunction is a common pathological feature in various retinal diseases. Dysregulation of RPE cell proteostasis and redox homeostasis is accompanied by increased reactive oxygen species generation during the impairment of phagocytosis, lysosomal and mitochondrial failure, and an accumulation of waste lipidic and protein aggregates. They are the inducers of RPE dysfunction and can trigger specific pathways of cell death. Autophagy serves as important mechanism in the endogenous defense system, controlling RPE homeostasis and survival under normal conditions and cellular responses under stress conditions through the degradation of intracellular components. Impairment of the autophagy process itself can result in cell death. In this review, we summarize the classical types of oxidative stress-induced autophagy in the RPE with an emphasis on autophagy mediated by molecular chaperones. Heat shock proteins, which represent hubs connecting the life supporting pathways of RPE cells, play a special role in these mechanisms. Regulation of oxidative stress-counteracting autophagy is an essential strategy for protecting the RPE against pathological damage when preventing retinal degenerative disease progression.

Myocardial ischemia/reperfusion (I/R)-induced cell death, such as autophagy and ferroptosis, is a major contributor to cardiac injury. Regulating cell death may be key to mitigating myocardial ischemia/reperfusion injury (MI/RI). Autophagy is a crucial physiological process involving cellular self-digestion and compensation, responsible for degrading excess or malfunctioning long-lived proteins and organelles. During MI/RI, autophagy plays both "survival" and "death" roles. A growing body of research indicates that ferroptosis is a type of autophagy-dependent cell death. This article provides a comprehensive review of the functions of autophagy and ferroptosis in MI/RI, as well as the molecules mediating their interaction. Understanding the link between autophagy and ferroptosis may offer new therapeutic directions for MI/RI, bearing significant clinical implications.

Environmental pollution represents a significant public health concern, with the potential health risks associated with environmental pollutants receiving considerable attention over an extended period. In recent years, a substantial body of research has been dedicated to this topic. Since the discovery of ferroptosis, an iron-dependent programmed cell death typically characterized by lipid peroxidation, in 2012, there have been significant advances in the study of its role and mechanism in various diseases. A growing number of recent studies have also demonstrated the involvement of ferroptosis in the damage caused to the organism by environmental pollutants, and the molecular mechanisms involved have been partially elucidated. The targeting of ferroptosis has been demonstrated to be an effective means of ameliorating the health damage caused by PM2.5, organic and inorganic pollutants, and ionizing radiation. This review begins by providing a summary of the most recent and important advances in ferroptosis. It then proceeds to offer a critical analysis of the health effects and molecular mechanisms of ferroptosis induced by various environmental pollutants. Furthermore, as is the case with all rapidly evolving research areas, there are numerous unanswered questions and challenges pertaining to environmental pollutant-induced ferroptosis, which we discuss in this review in an attempt to provide some directions and clues for future research in this field.

Drug resistance is a common challenge in clinical tumor treatment. A reduction in drug sensitivity of tumor cells is often accompanied by an increase in autophagy levels, leading to autophagy-related resistance. The effectiveness of combining chemotherapy drugs with autophagy inducers/inhibitors has been widely confirmed, but the mechanisms are still unclear. Ferroptosis and pyroptosis can be affected by various types of autophagy. Therefore, ferroptosis and pyroptosis have crosstalk via autophagy, potentially leading to a switch in cell death types under certain conditions. As two forms of inflammatory programmed cell death, ferroptosis and pyroptosis have different effects on inflammation, and the cGAS-STING signaling pathway is also involved. Therefore, it also plays an important role in the progression of some chronic inflammatory diseases. This review discusses the relationship between autophagy, ferroptosis and pyroptosis, and attempts to uncover the reasons behind the evasion of tumor cell death and the nature of drug resistance.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Ferroptosis and autophagy are two main forms of regulated cell death (RCD). Ferroptosis is a newly identified RCD driven by iron accumulation and lipid peroxidation. Autophagy is a self-degradation system through membrane rearrangement. Autophagy regulates the metabolic balance between synthesis, degradation and reutilization of cellular substances to maintain intracellular homeostasis. Numerous studies have demonstrated that both ferroptosis and autophagy play important roles in cancer pathogenesis and cancer therapy. We also found that there are intricate connections between ferroptosis and autophagy. In this article, we tried to clarify how different kinds of autophagy participate in the process of ferroptosis and sort out the common regulatory pathways between ferroptosis and autophagy in cancer. By exploring the complex crosstalk between ferroptosis and autophagy, we hope to broaden horizons of cancer therapy.

Micronutrient (MN) status alterations (both depletion and deficiency) are associated with several complications and worse outcomes in critically ill patients. On the other side of the spectrum, improving MN status has been shown to be a potential co-adjuvant therapy. This review aims to collect existing data to better guide research in the critical care setting. This narrative review was conducted by the European Society of Intensive Care Medicine Feeding, Rehabilitation, Endocrinology, and Metabolism MN group. The primary objective was to identify studies focusing on individual MNs in critically ill patients, selecting the MNs that appear to be most relevant and most frequently investigated in the last decade: A, B1, B2, B3, B6, folate, C, D, E, copper, iron, selenium, zinc, and carnitine. Given the limited number of interventional studies for most MNs, observational studies were included. For each selected MN, the review summarizes the main form and functions, special needs and risk factors, optimal treatment strategies, pharmacological dosing, and clinical implications all specific to critically ill patients. A rigorous rebalancing of research strategies and priorities is needed to improve clinical practice. An important finding is that high-dose monotherapy of MNs is not recommended. Basal daily needs must be provided, with higher doses in diseases with known higher needs, and identified deficiencies treated. Finally, the review provides a list of ongoing trials on MNs in critically ill patients and identifies a priority list of future research topics.

Oxidative stress is caused by the accumulation of reactive oxygen species (ROS) and the depletion of free radical scavengers, which is closely related to ferroptosis in diseases. Quercetin, as a natural flavonoid compound, has been reported to have multiple pharmacological effects on the basis of its anti-oxidative and anti-ferroptotic activities. This study was designed to explore the specific mechanism of quercetin against ferroptosis induced by hydrogen peroxide (H2O2).

The HT22 cells (mouse hippocampal neuronal cells) treated with 40 μg·ml-1 H2O2 were used to investigate the role of ferroptosis in oxidative stress damage and the regulation of quercetin (7.5, 15, 30 μmol·l-1), as evidenced by assessments of cell viability, morphological damage, Fe2+ accumulation, and the expressions of ferroptotic-related proteins. The changes in the expression levels of glutathione peroxidase 4 (GPX4), heat shock cognate protein 70 (HSC70), lysosomal-associated membrane protein 2a (LAMP-2a), and heat shock protein (HSP90) were assessed by qPCR, western blotting (WB) and immunofluorescence (IF) assays. Additionally, the interactions of GPX4, HSC70, LAMP-2a, and HSP90 were examined by co-immunoprecipitation (Co-IP) assay to elucidate the impact of quercetin on the degradation pathway of GPX4 and the CMA pathway. To further explore the regulatory mechanism of quercetin, the si-LAMP-2a and HSP90 mutant cells were conducted.

Pretreatment with 30 μmol·l-1 quercetin for 6 h significantly enhanced the survival rate (p < 0.05), maintained cell morphology, and inhibited Fe2+ levels in HT22 cells exposed to H2O2 (40 μg·ml-1). HT22 cells under oxidative stress showed lower expressions of GPX4 and ferritin heavy chain 1 (FTH1), and a higher level of Acyl-CoA synthetase long-chain family member 4 (ACSL4) (p < 0.05). And quercetin significantly reversed the expressions of these ferroptotic proteins (p < 0.05). Moreover, the autophagic lysosomal pathway inhibitor CQ effectively increased the expression of GPX4 in oxidative stress cell model. Further study showed that H2O2 increased the activity of macroautophagy and chaperone-mediated autophagy (CMA), while quercetin notably suppressed the levels of microtubule-associated protein light chain 3 Ⅱ (LC3 Ⅱ), LAMP-2a, and the activity of lysosomes (p < 0.01). Additionally, quercetin disrupted the interactions of GPX4, HSC70, and LAMP-2a, reduced cellular levels of CMA by decreasing the cleaved HSP90 (c-HSP90), and these effects were reversed in the R347 mutant HT22 cells.

Quercetin has a significantly protective effect on oxidative stress cell model through the inhibition on ferroptosis, which is related to the degradation of GPX4 via CMA. And quercetin decreases the level of c-HSP90 induced by H2O2 to reduce the activity of CMA by binding to R347 of HSP90.

Cells rely on autophagy for the degradation and recycling of damaged proteins and organelles. Chaperone-mediated autophagy (CMA) is a selective process targeting proteins for degradation through the coordinated function of molecular chaperones and the lysosome‑associated membrane protein‑2A receptor (LAMP2A), pivotal in various cellular processes from signal transduction to the modulation of cellular responses under stress. In the present review, the intricate regulatory mechanisms of CMA were elucidated through multiple signaling pathways such as retinoic acid receptor (RAR)α, AMP‑activated protein kinase (AMPK), p38‑TEEB‑NLRP3, calcium signaling‑NFAT and PI3K/AKT, thereby expanding the current understanding of CMA regulation. A comprehensive exploration of CMA's versatile roles in cellular physiology were further provided, including its involvement in maintaining protein homeostasis, regulating ferroptosis, modulating metabolic diversity and influencing cell cycle and proliferation. Additionally, the impact of CMA on disease progression and therapeutic outcomes were highlighted, encompassing neurodegenerative disorders, cancer and various organ‑specific diseases. Therapeutic strategies targeting CMA, such as drug development and gene therapy were also proposed, providing valuable directions for future clinical research. By integrating recent research findings, the present review aimed to enhance the current understanding of cellular homeostasis processes and emphasize the potential of targeting CMA in therapeutic strategies for diseases marked by CMA dysfunction.

Ferroptosis is a type of cell death that multiple mechanisms and pathways contribute to the positive and negative regulation of it. For example, increased levels of reactive oxygen species (ROS) induce ferroptosis. ferroptosis unlike apoptosis, it is not dependent on caspases, but is dependent on iron. Exosomes are membrane-bound vesicles with a size of about 30 to 150 nm, contain various cellular components, including DNA, RNA, microRNAs (miRNAs), lipids, and proteins, which are genetically similar to their cells of origin. Exosomes are found in all bodily fluids, including blood, saliva, and urine. Cells often release exosomes after their fusion with the cell membrane. They play an important role in immune regulation and cell-cell communication. miRNAs, which are noncoding RNAs with a length of about 18 to 24 nucleotides, are involved in regulating gene expression after transcription. Emerging data suggests that exosomal miRNAs are implicated in various pathophysiological mechanisms of cells, including metastasis, drug resistance, and cell death. In addition, functional studies have indicated that exosomal miRNAs can play a key role in the modulation of cell death by regulating ferroptosis. Therefore, in this review, given the importance of exosomal miRNAs in ferroptosis, we decided to elucidate the relationship between exosomal miRNAs and ferroptosis in various diseases.

Background: Diabetic liver injury is a serious complication due to the lack of effective treatments and the unclear pathogenesis. Ferroptosis, a form of cell death involving reactive oxygen species (ROS)-dependent lipid peroxidation (LPO), is closely linked to autophagy and diabetic complications. Therefore, this study is aimed at investigating the role of autophagy in regulating ferroptosis by modulating the degradation of acyl-CoA synthetase long-chain family member 4 (ACSL4) in diabetic hepatocytes and its potential impact on diabetic liver injury. Methods: Initially, ferroptosis and autophagy were assessed in liver tissues from streptozotocin-induced diabetic rats and in palmitic acid (PA)-treated LO2 cells. Subsequently, the study focused on elucidating the regulatory role of autophagy in mediating ferroptosis through the modulation of ACSL4 expression in PA-treated LO2 cells. Results: The results demonstrated that ACSL4-mediated ferroptosis and inhibition of autophagy were observed in diabetic hepatocytes in vivo and in PA-treated LO2 cells. Additionally, the ferroptosis inhibitor was able to mitigate the PA-induced cell death in LO2 cells. Mechanistically, the stability and expression level of the ACSL4 protein were upregulated and primarily degraded via the autophagy-lysosome pathway in PA-treated LO2 cells. The use of the autophagy inhibitor 3-methyladenine (3-MA) and the inducer rapamycin further demonstrated that autophagy regulated ferroptosis by mediating ACSL4 degradation, highlighting its critical role in diabetic liver injury. Conclusions: These results elucidate the roles of ferroptosis, autophagy, and their interactions in the pathogenesis of diabetic liver injury, offering potential therapeutic targets. Furthermore, they shed light on the pathogenesis of ferroptosis and other diabetic complications.

Diabetic kidney disease (DKD), one of the most prevalent microvascular complications of diabetes, arises from dysregulated glucose and lipid metabolism induced by hyperglycemia, resulting in the deterioration of renal cells such as podocytes and tubular epithelial cells. Programmed cell death (PCD), comprising apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis, represents a spectrum of cell demise processes intricately governed by genetic mechanisms in vivo. Under physiological conditions, PCD facilitates the turnover of cellular populations and serves as a protective mechanism to eliminate impaired podocytes or tubular epithelial cells, thereby preserving renal tissue homeostasis amidst hyperglycemic stress. However, existing research predominantly elucidates individual modes of cell death, neglecting the intricate interplay and mutual modulation observed among various forms of PCD. In this comprehensive review, we delineate the diverse regulatory mechanisms governing PCD and elucidate the intricate crosstalk dynamics among distinct PCD pathways. Furthermore, we review recent advancements in understanding the pathogenesis of PCD and explore their implications in DKD. Additionally, we explore the potential of natural products derived primarily from botanical sources as therapeutic agents, highlighting their multifaceted effects on modulating PCD crosstalk, thereby proposing novel strategies for DKD treatment.

Ferroptosis is a novel form of programmed cell death characterized by iron accumulation, lipid peroxidation, and a decline in antioxidant capacity, all of which are regulated by gene expression. The onset of numerous diseases is closely associated with ferroptosis. Common diseases affect a large population, reduce the quality of life, and impose an increased burden on the healthcare system. The role of ferroptosis in common diseases, its therapeutic potential, and even its translation into clinical drug treatments are currently significant research topics worldwide. This study preliminarily explores the theoretical basis of ferroptosis, its mechanism and treatment prospect in common diseases including ischaemia-reperfusion injury, inflammatory bowel diseases, liver fibrosis, acute kidney injury, diabetic kidney disease, stroke, Alzheimer's disease, cardiovascular disease, immune and cancer. This review provides a theoretical foundation for the further study and development of ferroptosis, as well as for the prevention and treatment of common diseases.

Excitatory neurotransmitter-induced neuronal ferroptosis has been implicated in multiple neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Although there are several reports pertaining to the pharmacological activities of biochanin A, the effects of this isoflavone on excitotoxicity-triggered neuronal ferroptosis remain unclear. In this study, we demonstrate that biochanin A inhibits ferroptosis of mouse hippocampal neurons induced by glutamate or the glutamate analog, kainic acid. Biochanin A significantly inhibited accumulation of intracellular iron and lipid peroxidation in glutamate- or kainic acid-treated mouse hippocampal neurons. Furthermore, biochanin A regulated the level of glutathione peroxidase 4, a master regulator of ferroptosis, by modulating its autophagy-dependent degradation. We observed that biochanin A reduced the glutamate-induced accumulation of intracellular iron by regulating expression of iron metabolism-related proteins including ferroportin-1, divalent metal transferase 1, and transferrin receptor 1. Taken together, these results indicate that biochanin A effectively inhibits hippocampal neuronal death triggered by glutamate or kainic acid. Our study is the first to report that biochanin A has therapeutic potential for the treatment of diseases associated with hippocampal neuronal death, particularly ferroptosis induced by excitatory neurotransmitter.

Ferroptosis, a novel form of cell death discovered in recent years, is typically accompanied by significant iron accumulation and lipid peroxidation during the process. This article systematically elucidates how tumor metabolic reprogramming affects the ferroptosis process in tumor cells. The paper outlines the basic concepts and physiological significance of tumor metabolic reprogramming and ferroptosis, and delves into the specific regulatory mechanisms of glucose metabolism, protein metabolism, and lipid metabolism on ferroptosis. We also explore how complex metabolic changes in the tumor microenvironment further influence the response of tumor cells to ferroptosis. Glucose metabolism modulates ferroptosis sensitivity by influencing intracellular energetic status and redox balance; protein metabolism, involving amino acid metabolism and protein synthesis, plays a crucial role in the initiation and progression of ferroptosis; and the relationship between lipid metabolism and ferroptosis primarily manifests in the generation and elimination of lipid peroxides. This review aims to provide a new perspective on how tumor cells regulate ferroptosis through metabolic reprogramming, with the ultimate goal of offering a theoretical basis for developing novel therapeutic strategies targeting tumor metabolism and ferroptosis.

Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.

Acute kidney injury (AKI) is a significant issue in public health, displaying a high occurrence rate and mortality rate. Ferroptosis, a form of programmed cell death (PCD), is characterized by iron accumulation and intensified lipid peroxidation. Recent studies have demonstrated the pivotal significance of ferroptosis in AKI caused by diverse stimuli, including ischemia-reperfusion injury (IRI), sepsis and toxins. Autophagy, a multistep process that targets damaged organelles and macromolecules for degradation and recycling, also plays an essential role in AKI. Previous research has demonstrated that autophagy deletion in proximal tubules could aggravate tubular injury and renal function loss, indicating the protective function of autophagy in AKI. Consequently, finding ways to stimulate autophagy has become a crucial therapeutic strategy. The recent discovery of the role of selective autophagy in influencing ferroptosis has identified new therapeutic targets for AKI and has highlighted the importance of understanding the cross-talk between autophagy and ferroptosis. This study aims to provide an overview of the signaling pathways involved in ferroptosis and autophagy, focusing on the mechanisms and functions of selective autophagy and autophagy-dependent ferroptosis. We hope to establish a foundation for future investigations into the interaction between autophagy and ferroptosis in AKI as well as other diseases.

Autophagy is intimately associated with the development of cardiomyopathy and has received widespread attention in recent years. However, no relevant bibliometric analysis is reported at present. In order to summarize the research status of autophagy in cardiomyopathy and provide direction for future research, we conducted a comprehensive, detailed, and multidimensional bibliometric analysis of the literature published in this field from 2004 to 2023.

All literatures related to autophagy in cardiomyopathy from 2004 to 2023 was collected from the Web of Science Core Collection, and annual papers, global publication trends, and proportion charts were analyzed and plotted using GraphPad price v8.0.2. In addition, CtieSpace [6.2.4R (64-bit) Advanced Edition] and VOSviewer (1.6.18 Edition) were used to analyze and visualize these data.

Two thousand two hundred seventy-nine papers about autophagy in cardiomyopathy were accessed in the Web of Science Core Collection over the last 20 years, comprising literatures from 70 countries and regions, 2208 institutions, and 10 810 authors. China contributes 56.32% of the total publications, substantially surpassing other countries, while the United States is ranked first in frequency of citations. Among the top 10 authors, six are from China, and four are from the United States. Air Force Military Medical University was the institution with the highest number of publications, while the Journal of Molecular and Cellular Cardiology (62 articles, 2.71% of the total) was the journal with the highest number of papers published in the field. Clustering of co-cited references and temporal clustering analysis showed that ferroptosis, hydrogen sulfide mitophagy, lipid peroxidation, oxidative stress, and SIRT1 are hot topics and trends in the field. The principal keywords are oxidative stress, heart, and heart failure.

The research on autophagy in cardiomyopathy is in the developmental stage. This represents the first bibliometric analysis of autophagy in cardiomyopathy, revealing the current research hotspots and future research directions in this field.