In a groundbreaking study published in Nature Metabolism, researchers have unveiled a crucial mechanism underlying the sex-specific progression of metabolic dysfunction-associated steatohepatitis (MASH), a severe and escalating phase of metabolic dysfunction-associated steatotic liver disease (MASLD). This liver condition represents a significant public health challenge worldwide, often advancing undetected until reaching end-stage liver diseases like cirrhosis and hepatocellular carcinoma, where treatment options are sorely limited. The new findings highlight the liver-selective receptor, GPR110, as a pivotal player in the sex disparity observed in MASH, opening the door to the development of targeted, sex-specific therapeutic interventions.
MASH describes an inflammatory liver disease triggered by metabolic dysregulation and fat accumulation within the liver. While MASLD incidence has surged globally in parallel with obesity and type 2 diabetes pandemics, the mechanistic details about why the disease progresses differently in males and females have remained elusive. This latest research reveals a distinctive role for GPR110, a G-protein-coupled receptor (GPCR) expressed selectively in hepatocytes, that differentially influences the disease course in male and female subjects.
The team employed hepatocyte-specific Gpr110 knockout mouse models to dissect the receptor’s role in MASH. Strikingly, female mice lacking Gpr110 in their liver cells exhibited marked protection against MASH. This sex-dependent protective effect was absent in male mice, suggesting an intrinsic biological divergence modulated by GPR110’s signaling. This discovery challenges the conventional one-size-fits-all approach to liver metabolic disease and calls attention to the importance of sex as a biological variable in future research and drug development.
Complementing their experimental model, the researchers analyzed genetic data identifying a variant of the GPR110 gene, known as rs937057 (a thymine to cytosine substitution), significantly associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. This variant highlights a genetic predisposition component modulated through GPR110, pointing to the receptor’s potential as both a biomarker and a target for precision medicine in female populations.
Delving deeper into the molecular mechanisms, the investigation uncovered that the hepato-protective phenotype in female mice hinges on the presence and functional integrity of hepatic estrogen receptor alpha (Esr1). When Esr1 expression was knocked down in the liver, the protective benefits conferred by Gpr110 deletion were nullified. This indicates that GPR110 operates through modulating the estrogen receptor signaling axis, tightly linking metabolic dysfunction in the liver with hormonal regulation that differs between sexes.
At the biochemical level, the researchers demonstrated that GPR110 couples explicitly to the Gα_s protein subunit, which activates protein kinase A (PKA). This cascade leads to phosphorylation of the nuclear factor of activated T cells 2 (NFAT2), a transcription factor crucial in various cellular processes. Phosphorylated NFAT2 is hindered from translocating into the nucleus, thereby suppressing its capacity to drive Esr1 gene transcription in hepatocytes. Consequently, GPR110 activation results in a downregulation of estrogen receptor alpha signaling, diminishing the liver’s estrogen sensitivity and exacerbating MASH pathogenesis predominantly in females.
This elegant mechanistic insight not only clarifies GPR110’s role in hepatic metabolic regulation but also explains the observed sex differences in MASH progression. Women’s livers appear more sensitive to estrogen receptor signaling, which normally confers a protective effect. GPR110, by attenuating this pathway, inadvertently promotes disease development. The absence of this signaling in males suggests alternate pathogenic routes underlying their disease phenotype, further underscoring the complexity of metabolic liver disease.
The translational implications of these findings are profound. Therapeutic strategies aimed at inhibiting GPR110 function present a novel avenue for sex-specific intervention in MASH. Targeting this receptor selectively in hepatocytes could restore estrogen receptor alpha activity in women, thereby mitigating the progression of liver inflammation and fibrosis characteristic of MASH. Such approaches could revolutionize the currently limited treatment landscape for this increasingly prevalent disease.
Moreover, genetic screening for the rs937057 variant might allow identification of high-risk female individuals for early intervention and personalized treatment plans. Integration of genotype-guided therapy could enhance clinical outcomes and reduce the burden of advanced liver disease. The study also invites further research into whether modulation of GPR110 signaling can synergize with other therapeutic agents to amplify hepatoprotective effects.
Beyond its immediate clinical implications, this work sets a precedent for investigating other GPCRs in the liver and other metabolic organs. GPR110 exemplifies how sex hormones interact intricately with metabolic pathways, influencing disease susceptibility and progression. Investigating similar receptors and their downstream signaling networks can unveil additional molecular targets vital for combating metabolic disorders that display sex biases.
To ensure clinical relevance, future studies will need to explore GPR110’s role in human liver tissue and examine the receptor’s expression and function across diverse populations and metabolic conditions. Longitudinal studies could elucidate the receptor’s involvement in disease progression and response to lifestyle or pharmacological interventions. Additionally, the safety and efficacy of GPR110 antagonists in preclinical models must be rigorously evaluated before contemplating clinical trials.
In summary, this pivotal research elucidates the liver-specific G-protein-coupled receptor GPR110 as a key determinant of sex-specific differences in metabolic dysfunction-associated steatohepatitis. By selectively modulating hepatic estrogen receptor alpha signaling through a novel Gα_s–PKA–NFAT2 axis, GPR110 influences the susceptibility and severity of MASH primarily in females. These insights expand our understanding of the molecular underpinnings of liver metabolic diseases and pave the way for sex-specific therapeutic innovations addressing this growing global health challenge.
As metabolic liver diseases continue to afflict millions worldwide, advancements such as those presented in this study are essential. They not only decode complex biological interactions but also translate into tangible clinical benefits through precision medicine. The sex disparity unveiled here serves as a reminder that nuanced, mechanistically guided approaches are crucial in developing effective treatments tailored to individual biological contexts.
Ongoing efforts to target GPR110 could revolutionize the management of MASH and potentially other metabolic conditions with sex-linked disparities. Such breakthroughs herald a new era of personalized hepatology, emphasizing hormone receptor crosstalk and receptor pharmacology as frontlines in combating metabolic syndrome’s hepatic manifestations. This study thus represents a beacon of hope amid the escalating global burden of liver disease.
Subject of Research: Sex-specific mechanisms in metabolic dysfunction-associated steatohepatitis involving hepatic GPR110 and estrogen receptor alpha signaling.
Article Title: Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.
Article References:
Yang, F., Wang, W., Qiu, F. et al. Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling. Nat Metab (2026). https://doi.org/10.1038/s42255-025-01436-1
Image Credits: AI Generated
