Fanlian Huazhuo formula: A promising therapeutic approach for metabolic associated steatotic liver disease

Abstract

This article reviews the study, “Fanlian huazhuo formula alleviates high-fat-diet-induced nonalcoholic fatty liver disease by modulating autophagy and lipid synthesis signaling pathway” published in the World Journal of Gastroenterology. The study explores the therapeutic potential of Fanlian Huazhuo formula (FLHZF) in treating metabolic-associated steatotic liver disease (MASLD), demonstrating that FLHZF reduces lipid accumulation, oxidative stress, and liver injury in MASLD models by modulating key signaling pathways involved in lipid metabolism and autophagy. This editorial emphasizes the potential of FLHZF as a treatment for MASLD and calls for further research to verify its clinical efficacy.

Key Words: Fanlian Huazhuo formula; Metabolic associated steatotic liver disease; Autophagy; Lipid metabolism; Oxidative stress

Core Tip: This article highlights the key findings of a study that Fanlian Huazhuo formula (FLHZF) is effective in treating metabolic-associated steatotic liver disease (MASLD) by reducing lipid accumulation, oxidative stress, and liver injury. FLHZF achieves these benefits by modulating autophagy and lipid metabolism pathways. These results underscore FLHZF’s potential as a therapeutic option for MASLD and emphasize the requirement for further clinical trials to validate its efficacy and safety in larger patient populations.

TO THE EDITOR

Metabolic-associated steatotic liver disease (MASLD) is a widespread condition marked by the excessive accumulation of fat in the liver, unrelated to alcohol consumption. It is strongly linked to metabolic disorders such as obesity, type 2 diabetes mellitus (T2DM), and cardiovascular diseases, making it a significant public health concern. As MASLD progresses, it can lead to more severe liver conditions, including non-alcoholic steatohepatitis (NASH) and cirrhosis[1]. Recent research has focused on exploring novel therapeutic strategies to effectively manage MASLD. One promising avenue is the application of traditional Chinese medicine (TCM), which has shown potential in treating various metabolic disorders. For example, the Huanglian-Hongqu herb pair has been found to improve MASLD by modulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/NOD-like receptor protein 3 (NLRP3) pathway[2]. Additionally, other TCM formulations such as Fufang Fanshiliu Decoction and Gynostemma pentaphyllum have been reported to alleviate metabolic disorders by influencing inflammatory responses and lipid metabolism[3,4]. Fanlian Huazhuo formula (FLHZF), a traditional Chinese herbal formula, has been recognized for its positive effects on conditions like T2DM. However, its impact on MASLD has not been extensively studied. The research conducted by Niu et al[1] makes a valuable contribution to this area by examining FLHZF's potential to mitigate MASLD through mechanisms such as the modulation of lipid metabolism, reduction of oxidative stress, and activation of autophagy[1]. This article aims to contextualize the findings of the Niu et al’s study within the broader MASLD research landscape, emphasizing FLHZF’s relevance as a potential therapeutic option[1]. The implications for future research and clinical practice will be discussed, with a focus on integrating traditional and modern approaches to effectively manage MASLD. The potential of TCM, particularly FLHZF, in offering a complementary treatment strategy for MASLD underscores the need for continued exploration and validation through rigorous scientific studies.

Significance of FLHZF in the treatment of MASLD

FLHZF has been a cornerstone of TCM, particularly in managing metabolic disorders like T2DM. Recently, its potential in treating liver dysfunction, especially MASLD, has garnered significant attention. Emerging research highlights FLHZF’s multifaceted therapeutic effects on key pathological mechanisms of MASLD, making it a promising treatment option. Niu et al[1] conducted preclinical studies using animal models of high-fat diet-induced MASLD in mice, which closely mimic the human disease. Their findings revealed that FLHZF significantly alleviated MASLD by modulating lipid metabolism and enhancing autophagy. This led to a marked reduction in triglyceride synthesis and accumulation within liver tissues—critical pathogenic features of MASLD[1]. Additionally, FLHZF demonstrated strong antioxidant properties, which help mitigate oxidative stress, a major contributor to liver injury in MASLD. By protecting hepatic cells from oxidative damage and reducing inflammation, FLHZF further preserved liver function[1,2]. Beyond its effects on lipid metabolism and oxidative stress, FLHZF also targeted other pathways involved in MASLD progression. For instance, Li et al[3] discovered that components of FLHZF modulate gut microbiota composition, reducing endotoxin levels and systemic inflammation, both of which play crucial roles in MASLD. By addressing gut-liver interactions, FLHZF enhances its effectiveness in reducing liver inflammation[3]. Comparative studies with other TCM formulations, such as the Huanglian-Hongqu herb pair, further support the idea that TCM approaches like FLHZF offer unique advantages in treating MASLD. These herbal formulations, including FLHZF, have been shown to reduce liver fat by influencing key pathways, such as NF-κB/NLRP3, which regulate inflammatory responses[2]. This underscores the holistic benefits of TCM in addressing both metabolic and inflammatory processes in liver diseases. Overall, FLHZF’s significance in MASLD treatment lies in its ability to address multiple pathogenic factors simultaneously. By reducing lipid accumulation, alleviating oxidative stress, and modulating inflammatory responses and gut microbiota, FLHZF offers a comprehensive, multifaceted treatment approach. This not only improves liver function but also lowers the risk of progression to more severe liver conditions such as NASH and cirrhosis[1,3].

Mechanistic insights into FLHZF 's action

Recent studies have shed light on how FLHZF modulates key signaling pathways involved in the pathology of MASLD. One of the primary mechanisms through which FLHZF exerts its therapeutic effects is by regulating the AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein 1C (SREBP-1C) pathway, which is crucial for lipid metabolism. FLHZF enhances AMPK activation by promoting its phosphorylation while simultaneously suppressing SREBP-1C, a transcription factor responsible for fatty acid and triglyceride synthesis. By inhibiting downstream targets of SREBP-1C, such as fatty acid synthase and acetyl-CoA carboxylase 1, FLHZF effectively reduces triglyceride synthesis and lipid accumulation in the liver[1]. In addition to modulating lipid metabolism, FLHZF plays a significant role in reducing oxidative stress, a key factor in MASLD progression. The formula lowers reactive oxygen species levels in the liver and boosts the activity of antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, both essential for neutralizing oxidative damage. This reduction in oxidative stress helps prevent hepatocellular injury and inflammation, thereby protecting liver function[1]. Another crucial aspect of FLHZF's mechanism is its ability to promote autophagy, the process by which cells clear lipid droplets and damaged components. Autophagy activation is essential in MASLD for mitigating lipid accumulation. FLHZF increases the expression of autophagy markers, such as LC3A/B, while concurrently enhancing AMPK phosphorylation. This suggests that the formula not only prevents lipid buildup through metabolic regulation but also facilitates the removal of excess lipids, thereby reducing liver damage[5]. By modulating the AMPK/SREBP-1C pathway, reducing oxidative stress, and promoting autophagy, FLHZF addresses both the metabolic and cellular dysfunctions that contribute to MASLD pathogenesis. These multifaceted mechanisms highlight FLHZF's potential as a comprehensive therapeutic option for MASLD management[1].

Comparison with existing treatments and future directions

A comparative analysis of FLHZF with established treatments for MASLD, such as fenofibrate, shows that FLHZF demonstrates superior efficacy in several key areas. These include reducing weight gain, improving abdominal fat index, and normalizing serum alanine transaminase levels[1]. While fenofibrate and similar pharmacological treatments primarily focus on lowering lipid levels, they often fail to address the broader metabolic and cellular dysfunctions associated with MASLD (Table 1). In contrast, FLHZF modulates multiple pathways, including AMPK/SREBP-1C, autophagy, and oxidative stress, providing a more comprehensive therapeutic approach. In addition to fenofibrate, other conventional treatments like glucagon-like peptide-1 (GLP-1) receptor agonists and Vitamin E have demonstrated efficacy in MASLD management. GLP-1 analogues, which improve insulin sensitivity and reduce hepatic steatosis, are gaining attention in MASLD treatment. However, while these treatments effectively target metabolic regulation, they often do not address key cellular processes like autophagy and oxidative stress. By comparison, FLHZF targets both metabolic pathways and cellular damage, offering a more holistic approach to liver protection[5]. Beyond pharmacological treatments, FLHZF’s potential also compares favorably with other TCM formulations, such as the Huanglian-Hongqu herb pair. Studies show that the Huanglian-Hongqu pair improves MASLD via the NF-κB/NLRP3 pathway, reducing inflammation and lipid accumulation[2]. While FLHZF shares these mechanisms by modulating both autophagy and inflammatory pathways, its broader influence on lipid metabolism and oxidative stress may offer superior efficacy. Moreover, integrating FLHZF with modern treatments could optimize therapeutic outcomes by enhancing anti-inflammatory and antioxidative effects[3]. Despite these promising findings, several areas warrant further exploration. A key gap is the lack of data on gender-specific responses to FLHZF. MASLD progression and treatment responses can differ significantly between males and females due to hormonal and metabolic factors. Future studies should focus on exploring these potential gender-specific variations, which could lead to more personalized treatment protocols. Also, the long-term safety and efficacy of FLHZF in MASLD management have not been fully established. Clinical trials assessing FLHZF’s effects over extended periods are necessary to evaluate its safety profile, particularly regarding potential toxicities or side effects when combined with conventional treatments. Understanding FLHZF’s long-term impact on both liver function and overall metabolic health is crucial for validating its role in modern MASLD management[1]. Another promising area for future research is investigating the synergistic effects of FLHZF when combined with established pharmacological treatments. For instance, combining FLHZF with GLP-1 analogues or Vitamin E could yield additive or synergistic benefits, improving metabolic regulation, lipid clearance, and reducing oxidative stress more effectively than either treatment alone[5]. Such combinations could pave the way for more comprehensive, individualized treatment plans tailored to each patient’s metabolic profile. Additionally, understanding how FLHZF interacts with the gut microbiota, which plays a pivotal role in MASLD progression, is crucial. Studies suggest that herbal formulas like FLHZF can modulate gut microbiota composition, reducing endotoxin levels and systemic inflammation[3]. Future research should delve deeper into these gut-liver interactions to further optimize the therapeutic potential of FLHZF. Overall, FLHZF presents a promising, multifaceted treatment option for MASLD by targeting lipid metabolism, oxidative stress, and autophagy. However, to fully realize its therapeutic potential, future research should prioritize comprehensive clinical trials, gender-specific responses, and synergistic effects with conventional therapies. As well, investigating the long-term safety and efficacy of FLHZF will be essential to establishing it as a viable treatment in modern MASLD management.

Table 1 Comparative analysis of Fanlian Huazhuo formula and existing metabolic associated steatotic liver disease treatments: Mechanisms, efficacy, and future research directions¹.

Aspect	Fanlian Huazhuo formula	Existing metabolic associated steatotic liver disease treatments
Mechanism of action	Modulates autophagy and lipid synthesis signaling pathways[1]	Varies: Inflammation modulation, autophagy regulation, lipid metabolism, and gut microbiota management[1-10]
Key pathways targeted	Autophagy, lipid synthesis pathways[1]	NF-κB/NLRP3[2], IRE1-α/IKKβ/NF-κB[6], AMPK[7], TLR4/NF-κB[7], PPARα-RXRα[11]
Efficacy	Alleviates high-fat diet-induced metabolic associated steatotic liver disease; reduces hepatic steatosis and inflammation[1]	Demonstrated effectiveness in reducing liver fat, inflammation, and improving liver function[3,6,9]
Comparison with other treatments	Promising in balancing autophagy and lipid metabolism, potentially offering a unique approach compared to conventional drugs	Existing treatments such as Huanglian-Hongqu[2], Fufang Fanshiliu Decoction[3], and Gynostemma pentaphyllum[4] show efficacy in different pathways, suggesting a multi-faceted approach
Clinical evidence	Evidence from animal studies; human clinical trials are needed[1]	Extensive clinical and preclinical evidence supports their efficacy[2,3]
Current limitations	Lack of extensive human clinical trial data; mechanism needs further elucidation[1]	Some treatments may have limited long-term efficacy or side effects; continued research needed for optimization[2,5]
Future research directions	Further human clinical trials to validate efficacy; exploration of long-term effects and safety profiles[1]	Ongoing studies to explore new drug combinations, personalized treatments, and mechanism-based therapies. Research into combination therapies and natural products is also ongoing[6,12]

¹This table presents a comparative analysis of Fanlian Huazhuo formula (FLHZF) and other treatments for metabolic associated steatotic liver disease (MASLD).

It outlines the mechanisms through which FLHZF and other therapies exert their effects on MASLD, focusing on key signaling pathways and molecular targets. FLHZF is noted for its impact on autophagy and lipid synthesis pathways, while other treatments address various pathways, including nuclear factor-kappa B (NF-κB)/NOD-like receptor protein 3, inositol-requiring enzyme 1 alpha/inhibitor of kappa B kinase beta/NF-κB, AMP-activated protein kinase, Toll-like receptor 4/NF-κB, and peroxisome proliferator-activated receptor alpha/retinoid X receptor alpha. The table also summarizes the observed efficacy of these treatments in improving hepatic steatosis, inflammation, and overall liver function. It highlights how FLHZF compares with other therapies in terms of approach and potential benefits, the level of clinical evidence supporting each treatment, and current limitations. Future research directions are suggested to enhance understanding and effectiveness, emphasizing the need for further clinical trials and exploration of combination therapies.

CONCLUSION

The study on FLHZF presents strong evidence of its therapeutic potential for MASLD. By targeting key pathological aspects of MASLD, such as lipid metabolism, oxidative stress, and autophagy, FLHZF offers a comprehensive approach to treatment. Its ability to modulate the AMPKα/SREBP-1C signaling pathway, reduce oxidative damage, and activate autophagy underscores its promise as an effective intervention for MASLD[1]. However, despite these encouraging findings, further research is essential to fully establish FLHZF's clinical efficacy and safety. Comprehensive clinical trials are needed to evaluate its long-term effects, potential side effects, and interactions with other treatments. Studies have already demonstrated that TCM formulas like FLHZF can influence lipid synthesis and autophagy, providing a strong foundation for clinical exploration of these mechanisms[2]. Expanding research to include diverse patient populations and investigating additional mechanisms of action will deepen our understanding of FLHZF’s role in MASLD management. Moreover, combining traditional formulas with modern pharmacological treatments has been shown to improve outcomes in liver diseases. For instance, the Huanglian-Hongqu herb pair has demonstrated efficacy in MASLD by modulating the NF-kappaB/NLRP3 pathway, suggesting that similar integrative approaches could offer significant benefits[6]. Network pharmacology and molecular docking studies have also validated the therapeutic potential of various herb pairs in MASLD, emphasizing the relevance of these traditional formulas[5]. FLHZF represents a valuable addition to the therapeutic arsenal against MASLD, opening new avenues for treatment and contributing to the advancement of integrative liver disease management. The promising results of FLHZF, along with findings from related studies, highlight the potential of TCM in modern therapeutic strategies for MASLD. Continued investigation will help solidify FLHZF's role and optimize its application, potentially transforming the management of MASLD.