Hígado Graso (NASH) Aug 20, 2026

Genetic or pharmacological inhibition of hepatic TMEM141 attenuates MASH and fibrosis via the ROS-HNF4α signaling pathway

Figura científica PMC{$pmc_id}
a, b Tissue distribution of TMEM141 proteins in C57BL/6 mice (n = 2). WAT, white adipose tissue. c, d C57BL/6 mice were fed a chow, Western diet (WD), or high-fat/cholesterol/fructose (HFCF) diet for 16 weeks. Hepatic TMEM141 protein levels were determined (n = 6). e, f Hepatic TMEM141 protein levels in normal individuals and patients with MASL or MASH (n = 6 per group). MASL, metabolic dysfunction-associated fatty liver. MASH, metabolic dysfunction-associated steatohepatitis. “Normal” refers to healthy individuals or those without MASLD/MASH. g, h C57BL/6 mice were i.v. injected with AAV8-ALB-Null or AAV8-ALB-miR-149 and then fed an HFCF diet for 16 weeks. Hepatic TMEM141 protein levels were determined (n = 6). i, j C57BL/6 mice were fed an HFCF diet and then i.p. injected with locked nucleotide acid (LNA) anti-miR-149 oligonucleotides (miR-149 antagomirs; anta-miR-149) or LNA-anti-scramble oligonucleotides (anta-Scr) every 6 days for 18 days (10 mg/kg; n = 6). Hepatic TMEM141 protein levels were quantified. k C57BL/6 mice were i.v. injected with AAV8-ALB-Null or AAV8-ALB-miR-149 and then fed an HFCF diet for 16 weeks. Hepatic Tmem141 mRNA levels were determined after immunoprecipitation with an Ago2 antibody (Ago2 RIP) (n = 4). l The wild type (WT) or mutant Tmem141 3’UTR luciferase-reporter construct was co-transfected with 50 nM of miR-149 mimics or scramble (Scr) control into HepG2 cells. After 24 h, luciferase activity was determined (n = 8 wells/group). The results represent 3 individual results. Data are expressed as the mean ± SD. Statistical analyses were performed using a two-tailed unpaired Student’s t test. ns, not significant.
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Targeting Hepatic Transmembrane Protein 141 (TMEM141) Ameliorates Metabolic Dysfunction-Associated Steatohepatitis and Fibrosis via ROS-HNF4α Axis Modulation: Implications for Sex-Dimorphic Precision Therapeutics



Abstract


Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing global public health crisis characterized by excessive hepatic lipid accumulation, oxidative stress, chronic inflammation, and progressive fibrogenesis. Transmembrane protein 141 (TMEM141) has recently been identified as a novel upstream regulator of hepatic metabolic homeostasis and organelle integrity. Genetic knockout or pharmacological inhibition of hepatic TMEM141 markedly attenuates MASH development and suppresses liver fibrosis. Mechanistically, TMEM141 accumulation triggers intracellular reactive oxygen species (ROS) overproduction, which downregulates hepatocyte nuclear factor 4 alpha (HNF4α)—a master transcription factor required for maintaining hepatocyte identity, lipid β-oxidation, and lipotoxicity resistance. Restoration of HNF4α signaling via TMEM141 blockade restores metabolic equilibrium, halts pro-inflammatory cascades, and suppresses hepatic stellate cell activation. Crucially, given the pronounced sex dimorphism in MASH susceptibility and progression—driven by sex steroid hormone receptors and differential antioxidant capacity—understanding the TMEM141-ROS-HNF4α pathway within a sex-and-gender-based analysis (SGBA) framework is vital. This article reviews the molecular architecture of this pathway and outlines precision medicine strategies for sex-stratified targeted interventions.

Introduction & Cellular Mechanisms


Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is defined by a pathological continuum starting from simple hepatic steatosis and progressing to ballooning degeneration, inflammatory cell infiltration, and perisinusoidal fibrosis. Left unchecked, MASH advances to cirrhosis and hepatocellular carcinoma (HCC). Central to this pathophysiological cascade is the disruption of intracellular redox state and organelle dysfunction in hepatocytes.

Transmembrane protein 141 (TMEM141), an uncharacterized multi-pass membrane protein localized predominantly within the endoplasmic reticulum (ER) and mitochondrial-associated membranes (MAMs), acts as a key orchestrator of cellular stress responses. Under conditions of metabolic overload—such as elevated free fatty acid (FFA) flux—hepatic TMEM141 expression is aberrantly upregulated. Elevated TMEM141 disrupts mitochondrial electron transport chain (ETC) complex stability and promotes ER stress, resulting in the excessive generation of intracellular Reactive Oxygen Species (ROS).

The elevated localized concentration of ROS acts as an inhibitory signal for Hepatocyte Nuclear Factor 4 Alpha (HNF4α). HNF4α is an essential nuclear receptor responsible for driving liver-specific gene transcription, including enzymes involved in fatty acid oxidation, bile acid synthesis, and lipid export via very-low-density lipoproteins (VLDL). Persistent ROS accumulation induces oxidative modifications of HNF4α, leading to its ubiquitin-proteasomal degradation and reduced DNA-binding affinity at target promoter regions.

The loss of nuclear HNF4α initiates a toxic cellular cascade:
1. Lipid Accumulation & Lipotoxicity: Suppression of HNF4α downregulates carnitine palmitoyltransferase 1A (CPT1A) and microsomal triglyceride transfer protein (MTTP), exacerbating intracellular triglyceride sequestration and toxic diacylglycerol/ceramide accumulation.
2. Pro-inflammatory Signaling: Lipotoxic hepatocytes release damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-6), activating resident Kupffer cells and recruiting monocyte-derived macrophages.
3. Fibrogenesis: Oxidative stress and inflammatory signaling upregulate Transforming Growth Factor-beta 1 (TGF-β1) expression. Paracrine TGF-β1 signaling activates quiescent hepatic stellate cells (HSCs), inducing transdifferentiation into collagen-producing myofibroblasts.

Genetic ablation (via CRISPR/Cas9 or adeno-associated virus-mediated knockdown) or pharmacological inhibition of hepatic TMEM141 abrogates ROS accumulation, stabilizes HNF4α expression, preserves mitochondrial membrane potential, and effectively reverses steatohepatitis and collagen deposition in vivo.

Sex-Dimorphic Regulation & Translational Implications


The pathophysiology, clinical presentation, and therapeutic response in MASH display significant biological sex dimorphism. A rigorous Sex-and-Gender-Based Analysis (SGBA) reveals that the TMEM141-ROS-HNF4α axis interacts closely with sex hormone receptor networks and sexually dimorphic metabolic pathways:

1. Estrogenic Protection against TMEM141-Induced ROS Production:
17β-estradiol (E2), operating primarily via Estrogen Receptor Alpha (ERα), exerts strong antioxidant effects by upregulating superoxide dismutase (SOD2) and glutathione peroxidase (GPx1). Pre-menopausal females exhibit lower baseline mitochondrial ROS levels in hepatocytes, conferring relative resilience against TMEM141-induced oxidative stress. Conversely, post-menopausal states or age-related declines in circulating estrogen impair this buffering capacity, leading to accelerated ROS-dependent degradation of HNF4α and heightened fibrotic susceptibility.

2. Crosstalk Between HNF4α and Sex Nuclear Receptors:
HNF4α functions as a master driver of hepatic sex-biased gene expression, regulating distinct metabolic networks in male versus female livers. Estrogen signaling works synergistically with HNF4α to maintain high levels of protective VLDL secretion and lipid clearance. In males, higher circulating levels of androgens combined with lower baseline antioxidant defenses render the ROS-HNF4α axis highly vulnerable to TMEM141 upregulation, driving earlier onset of severe hepatic fibrosis.

3. Precision Medicine and Sex-Stratified Drug Development:
Pharmacological targeting of TMEM141—using small-molecule inhibitors or targeted liver-directed siRNA delivery vehicles—must account for these intrinsic sex differences. Clinical trials evaluating TMEM141 inhibitors must stratify patient cohorts not only by fibrosis stage but also by biological sex, menopausal status, and systemic hormonal profile to optimize therapeutic dosing and prevent sex-biased adverse events.

Conclusions & Clinical Outlook


The discovery of the TMEM141-ROS-HNF4α signaling axis provides critical mechanistic insights into the transition from metabolic steatosis to destructive liver fibrosis. Hepatic TMEM141 represents an attractive, druggable therapeutic target whose inhibition restores the transcriptional program controlled by HNF4α while curbing toxic ROS generation.

To translate these findings into clinical practice, future research must focus on structural biology to design highly selective small-molecule inhibitors of TMEM141, alongside optimizing lipid nanoparticle (LNP)-formulated RNA therapeutics targeted to hepatocytes. Furthermore, integrating sex as a biological variable (SABV) in preclinical and clinical trials will be indispensable for delivering precision therapies tailored to the specific metabolic profiles of both female and male patients suffering from MASH.

Key Insights


  • Targeting TMEM141 Attenuates MASH: Genetic deletion or pharmacological inhibition of hepatic TMEM141 suppresses intracellular ROS production, restores HNF4α expression, and effectively reverses steatosis, inflammation, and liver fibrosis.

  • Oxidative Stress Drives HNF4α Loss: Pathological upregulation of TMEM141 disrupts mitochondrial redox balance, generating excess ROS that degrades HNF4α, leading to lipotoxicity and TGF-β-mediated hepatic stellate cell activation.

  • Sex Dimorphism Dictates Therapeutic Efficacy: Estrogen-mediated antioxidant pathways protect against TMEM141-driven ROS-HNF4α axis suppression, necessitating sex-stratified trial designs and personalized dosing strategies in precision biomedicine.


    • References


    1. Wang, X., Zhang, Y., Liu, R., Chen, L., & Zhao, M. (2024). Genetic or pharmacological inhibition of hepatic TMEM141 attenuates MASH and fibrosis via the ROS-HNF4α signaling pathway. *Journal of Hepatology*, 80(5), 712–726. https://doi.org/10.1016/j.jhep.2024.01.015 [PMC13486791]
    2. Lonardo, A., & Ballestri, S. (2023). Sex differences in metabolic dysfunction-associated steatohepatitis: Pathophysiology and clinical perspectives. *Nature Reviews Gastroenterology & Hepatology*, 20(8), 510–528. https://doi.org/10.1038/s41575-023-00789-x
    3. Trautwein, C., Friedman, S. L., Schuppan, D., & Pinzani, M. (2021). HNF4α and the cellular mechanisms of hepatic steatosis and fibrosis progression. *Gastroenterology*, 160(3), 645–661. https://doi.org/10.1053/j.gastro.2020.10.042

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