Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease frequently linked to vitamin D deficiency, which correlates with the severity of the disease and fibrosis. Although reduced dietary intake and sunlight exposure are known contributors, the effect of impaired hepatic vitamin D bioactivation remains unclear. CYP2R1, an enzyme in the liver, converts vitamin D into 25-hydroxyvitamin D (calcifediol), a crucial step in its activation. This study explored the impact of MASH-associated lipotoxicity on CYP2R1 expression and vitamin D metabolism. Analysis of human liver transcriptomic data revealed a significant reduction in CYP2R1 expression in MASH, particularly in advanced fibrosis stages. Similarly, murine models of MASH show decreased hepatic Cyp2r1 expression, elevated liver injury markers, and reduced circulating 25-hydroxyvitamin D levels. Furthermore, in vitro studies demonstrated that palmitic acid caused a dose-dependent decrease in CYP2R1 expression in human hepatocytes, indicating a cell-autonomous effect. Calcifediol significantly induced vitamin D receptor (VDR) expression in human hepatocytes and hepatic stellate cell lines, suggesting the role of intra-hepatic calcifediol in maintaining VDR signalling. These findings uncover lipotoxic repression of CYP2R1 as a previously unrecognized mechanism contributing to vitamin D deficiency and impaired hepatic VDR signalling in MASH, highlighting hepatic vitamin D bioactivation as a potential therapeutic target.

Vitamin D deficiency is highly prevalent in alcohol-associated liver disease and may contribute to metabolic and inflammatory dysregulation in alcoholic steatohepatitis (ASH). To examine the hepato-metabolic actions of vitamin D receptor (VDR) activation in ASH, we evaluated calcipotriol, a VDR agonist, in male C57BL/6N mice fed a 5% ethanol-containing Lieber-DeCarli diet. Calcipotriol (20 µg/kg) reduced intra-hepatic triglyceride accumulation and serum alanine aminotransferase activity, indicating attenuation of alcohol-induced liver injury. Integrated transcriptomic, metabolomic, and biochemical analyses showed that VDR agonism suppressed hepatic lipogenic programs, including de novo lipogenesis, and improved alcohol-induced metabolic derangements. Calcipotriol also reduced oxidative injury and endoplasmic reticulum stress, as evidenced by lower hepatic protein carbonyl content and reduced p-eIF2α, XBP1s, CHOP, ATF4, and BiP expression, together with diminished inflammasome-associated inflammatory signalling. Metabolomic profiling further showed partial restoration of hepatic metabolic homeostasis by calcipotriol, as evidenced by increased choline, uridine monophosphate, and taurine levels. These findings identify calcipotriol as an endocrine-metabolic modulator of ASH and support VDR activation as a mechanistically relevant therapeutic strategy for alcohol-induced liver injury.

Hepatic iron accumulation and toxicity is a frequent finding in chronic liver diseases such as hereditary hemochromatosis (HH), metabolic associated fatty liver disease (MASLD), alcoholic liver disease (ALD) and hepatitis C virus (HCV) infection, however, it's contribution to disease pathology is not fully understood. Here, using HepG2 cells we show that iron induced hepatocyte damage triggers the release of extracellular RNAs (eRNAs), which bind to the toll-like receptor 3 (TLR3), resulting in the production of pro-inflammatory cytokines. Furthermore, the inhibition of eRNA activity by RNase1 and TLR3 inhibitor significantly improved cell viability as well as NLRP3 and NF-kB-mediated inflammatory signalling. Therefore, eRNA antagonism could represent a novel therapeutic approach to reduce iron-induced inflammation in chronic liver diseases.

Background and aimsPre-emptive transjugular intrahepatic portosystemic shunt (pTIPSS) within 72 hours following acute oesophageal variceal bleeding has potential survival benefit. However, there is uncertainty whether pTIPSS is advantageous over standard of care (SOC) and long-term outcomes remain unstudied.ApproachPatients recruited to a Scottish randomised control trial were allocated to SOC or pTIPSS and had follow-up extended to 3 years. The primary outcome was 3-year transplant-free survival on intention to treat and per-protocol analysis.Results58 patients were initially recruited, 29 patients per group. Of the 29 in the pTIPSS group, only 23 received TIPSS placement due to logistical reasons. On intention to treat analysis, 3-year transplant-free survival rate in the SOC group was significantly higher than that of the pTIPSS group (55.2% vs 20.1%, p=0.006, HR 2.5, 95% CI 1.3 to 4.87). On per-protocol analysis, 3-year transplant-free survival rate in the SOC group was significantly higher than that of the pTIPSS group (55.2% vs 15.4%, p=0.03, HR 2.93, 95% CI 1.27 to 7.94). There were significantly higher rates of sepsis-related death or sepsis-induced liver failure-related death in the pTIPSS group compared with the SOC group (48.2% vs 3.6%, p<0.001, reciprocal of RR 13.0, 95% CI 2.46 to 75.45). There were no differences in other outcomes associated with portal hypertension on intention to treat analysis.ConclusionpTIPSS was associated with significantly reduced rates of transplant-free survival at 3 years compared with SOC. This may be due to higher rates of sepsis. Further large studies are required to validate these findings.

Alcoholic steatohepatitis (ASH) is characterized by hepatic steatosis, inflammation, and alcohol-induced liver damage in humans. G9a, a histone methyltransferase, serves as a multipotent regulator of gene expression and plays a significant role in hepatic drug metabolism and cellular stress. Although epigenetic alterations occur during alcoholic liver disease progression, G9a's precise contribution to ASH pathogenesis remains unclear. Using a murine model of ASH, we demonstrate that G9a expression is downregulated during ASH progression, and G9a pharmacological inhibition exacerbates ASH severity, shown by increased hepatic steatosis and serum ALT levels. Through an integrated transcriptomic and metabolomic approach, we show that loss of G9a activity in alcohol-exposed mice enhances hepatic expression of gene sets involved in cell cycle, cytoskeletal rearrangement, steroid biosynthesis, cellular stress, and proinflammatory pathways. Liver metabolomic analysis revealed that G9a inhibition increased nucleotide degradation, hepatic choline depletion, and enhanced branched-chain amino acid (BCAA) synthesis. These results suggest that G9a repression, through its effect on nucleotide, choline, and BCAA metabolism, blunts liver regenerative potential despite a repair commitment to alcohol, leading to increased hepatic toxicity and aggravated ASH phenotype. This study highlights G9a's critical role in modulating hepatic susceptibility to alcohol toxicity.

Metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic steatohepatitis (ASH) are severe forms of chronic liver disease, characterized by inflammation, oxidative stress, lipid dysregulation, and fibrosis. Epigenetic changes, including acetylation, methylation, phosphorylation, ubiquitination, sumoylation, and lactylation of histones, dynamically regulate gene expression by altering the chromatin structure. Emerging evidence highlights histone modifications as chief contributors to the pathogenesis of chronic liver diseases. Lactylation which is a novel post-translational modification (PTM) of histone, has been observed as a crucial contributor to liver physiology as well as pathobiology. This modification, characterized by the addition of lactate to lysine residues on histones, influences gene expression and cellular metabolism in the liver. Intriguingly, elevated lactate levels in the liver, resulting from either chronic alcohol consumption or a high-fat/fructose-rich diet, may promote histone lactylation, particularly at histone 3 at lysine 18 (H3K18), which facilitates the transcription of pro-inflammatory and fibrogenic genes. This process not only intensifies hepatic inflammation and fibrosis but also disrupts normal metabolic pathways, resulting in further liver damage. This review aims to elucidate the role of histone lactylation in MASH. Although a direct demonstration of histone lactylation in ASH has not yet been reported, the altered lactate metabolism in ASH suggests that histone lactylation may significantly contribute to its pathogenesis. Finally, we explore novel strategies targeting histone lactylation to mitigate liver injury and improve disease management in MASH and ASH.

Dehydroepiandrosterone (DHEA), a precursor of sex hormones, has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), with studies suggesting a strong correlation between DHEA levels and disease severity. In this study, we demonstrated that DHEA alleviated lipotoxicity-induced hepatic damage by promoting autophagy. Our findings demonstrate that DHEA-induced autophagy is mediated by estrogen receptor alpha (ER-α) and androgen receptor (AR) activation and protects hepatic cells against palmitate-induced apoptosis, steatosis, and inflammasome activation. DHEA treatment in a murine NASH model induced significant autophagy in the liver, further supporting the hepatoprotective role of DHEA. Collectively, our results identified DHEA as a pro-autophagic hormone with therapeutic potential for the treatment of lipotoxicity in NASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), are major global health issues involving metabolic dysfunction, hepatic lipotoxicity, and chronic inflammation. A key driver of MASH pathogenesis is sterile inflammation, a non-infectious immune response triggered by molecules that are released from injured or dying liver cells. These molecules termed as damage-associated molecular patterns (DAMPs), which activate innate immune receptors, such as Toll-like receptors (TLRs), NOD-like receptors, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to encourage inflammatory signaling, cytokine production, immune cell recruitment, and ultimately fibrogenic activation in MASH. Sterile inflammation sits at the crossroads of metabolic injury and immune activation in MASH and drives disease progression from simple fat build-up to irreversible liver damage. Targeting these sterile inflammatory pathways appears to be an attractive approach for halting or reversing hepatic inflammation and fibrogenic activation in MASH. Extracellular RNAs (eRNAs) have recently been identified as potent DAMPs that trigger sterile inflammation in MASH by engaging in TLR3 signaling. Furthermore, RNase1-based treatments have been proposed as novel therapeutic strategies to interrupt the self-sustaining loop of inflammatory signaling induced by eRNA in MASH. In this review, we discuss the key molecular mechanisms that fuel sterile inflammation in MASLD/MASH, highlighting eRNA as novel therapeutic targets to restrict inflammation in MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly referred to as non-alcoholic fatty liver disease, is a major cause of end-stage liver disease worldwide. Numerous studies have demonstrated that the liver is predominantly influenced by environmental and lifestyle risk factors that lead to obesity and diabetes, excessive alcohol consumption, and exposure to environmental pollutants. Microplastics (MPs) are a significant global concern, having been detected in human blood, lungs, kidneys, and liver, and may have deleterious effects on these tissues. Although the effects of MP exposure on the liver have only been partially elucidated, further research is necessary to integrate the direct and extrahepatic effects of MPs on the pathogenesis of MASLD. This review offers a comprehensive analysis of the impact of MPs on hepatic metabolism, including their effects on mitochondrial homeostasis and the endocrine system, with potential implications for the progression of MASLD.

Thyroid hormones (THs) are key hormones that regulate development and metabolism in mammals. In man, the major target tissues for TH action are the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action have been associated with genetic and endocrine diseases in man. Over the past few years, there has been renewed interest in TH action and the therapeutic potential of THs and thyromimetics to treat several metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. Recent advances in the development of tissue and TH receptor isoform-targeted thyromimetics have kindled new hope for translating our fundamental understanding of TH action into an effective therapy. This review provides a concise overview of the historical development of our understanding of TH action, its physiological and pathophysiological effects on metabolism, and future therapeutic applications to treat metabolic dysfunction. Sinha and Yen provide a comprehensive overview of thyroid hormones and their role in development and in regulation of whole-body metabolic homeostasis

Skeletal muscle wasting is a clinically proven pathology associated with Japanese encephalitis virus (JEV) infection; however, underlying factors that govern skeletal muscle damage are yet to be explored. The current study aims to investigate the pathobiology of skeletal muscle damage using a mouse model of JEV infection. Our study reveals a significant increment in viral copy number in skeletal muscle post-JEV infection, which is associated with enhanced skeletal muscle cell death. Molecular and biochemical analysis confirms NOX2-dependent generation of reactive oxygen species, leading to autophagy flux inhibition and cell apoptosis. Along with this, an alteration in mitochondrial dynamics (change in fusion and fission process) and a decrease in the total number of mitochondria copies were found during JEV disease progression. The study represents the initial evidence of skeletal muscle damage caused by JEV and provides insights into potential avenues for therapeutic advancement.

Alcoholic steatohepatitis (ASH) represents a critical stage in alcoholic liver disease (ALD), which significantly increases the risk of developing alcoholic hepatitis and cirrhosis. Currently, corticosteroids and alcohol abstinence remain the only available strategy to prevent or reverse ASH progression with no FDA approved drug therapy till date. Given the notable pathological similarities between ASH and metabolic dysfunction-associated steatohepatitis (MASH), repurposing drugs approved for MASH presents an attractive therapeutic approach to treat ASH. In this context, we evaluated the efficacy of Resmetirom, a recently approved drug for MASH, in a mouse model of ASH. Our findings demonstrate that Resmetirom, a liver-specific thyroid hormone analog, not only reduces hepatic steatosis but also markedly alleviates liver injury, oxidative stress, and inflammation associated with ASH. In summary, this study provides a proof-of-concept for the potential use of MASH drugs in treating ASH and establishes a foundation for future testing and clinical trials of Resmetirom, in patients with ASH.

The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

Lipotoxicity is a key pathological feature in the development of non-alcoholic steatohepatitis (NASH), which is characterized by liver injury, inflammation, and fibrosis. Although lipotoxicity has been shown to induce transcriptomic alterations in liver cells, the specific role of epigenetic regulators in NASH remains elusive. In this study, we demonstrate that pharmacological inhibition of histone methyltransferase G9a significantly worsens NASH progression in mice, as evidenced by increased hepatic cell death, inflammation, and fibrosis. Additionally, at a cellular level both genetic and pharmacological inhibition of G9a in HepG2 cells increased their susceptibility to palmitic acid-induced apoptosis and sub-cellular stress. Furthermore, treatment with G9a inhibitor enhanced TGF-β induced activation of primary human hepatic stellate cells (hHSCs), implicating the role of G9a in NASH pathobiology.

The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus–pituitary–thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics. Thyroid hormones, triiodothyronine and thyroxine, are vital for metabolic homeostasis, and regulate essential hepatic functions. This Review summarizes the current knowledge of the role of thyroid hormones in the liver and examines the development of thyromimetics for liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.

The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body’s behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as “circadian disruption”. This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.

Non-alcoholic steatohepatitis (NASH) is a clinically serious stage of non-alcoholic fatty liver disease (NAFLD). Histologically characterized by hepatocyte ballooning, immune cell infiltration, and fibrosis, NASH, at a molecular level, involves lipid-induced hepatocyte death and cytokine production. Currently, there are very few diagnostic biomarkers available to screen for NASH, and no pharmacological intervention is available for its treatment. In this study, we show that hepatocyte damage induced by lipotoxicity results in the release of extracellular RNAs (eRNAs), which serve as damage-associated molecular patterns (DAMPs) that stimulate the expression of pro-apoptotic and pro-inflammatory cytokines, aggravate inflammation, and lead to cell death in HepG2 cells. Furthermore, the inhibition of eRNA activity by RNase 1 significantly increases cellular viability and reduces NF-kB-mediated cytokine production. Similarly, RNase 1 administration significantly improves hepatic steatosis, inflammatory and injury markers in a murine NASH model. Therefore, this study, for the first time, underscores the therapeutic potential of inhibiting eRNA action as a novel strategy for NASH treatment.