INHBE

Official Full Name

inhibin subunit beta E

Organism

Homo sapiens

GeneID

83729

Background

This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate an inhibin beta subunit. Inhibins have been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. This gene may be upregulated under conditions of endoplasmic reticulum stress, and this protein may inhibit cellular proliferation and growth in pancreas and liver. [provided by RefSeq, Sep 2016]

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Detailed Information

The INHBE gene, encoding the inhibin βE subunit, is a member of the transforming growth factor-β (TGF-β) superfamily. This superfamily consists of structurally related, functionally diverse cytokines that play central roles in regulating growth, differentiation, apoptosis, and immune responses in multicellular organisms. The initial translation product of INHBE is a precursor protein, which requires proteolytic cleavage to generate the biologically active mature βE subunit. This mature βE subunit can form a disulfide-linked dimer with a common α subunit to produce inhibin E or combine with other β subunits to generate activins. Inhibins and activins functionally antagonize each other, forming a finely tuned endocrine regulatory network.

From an evolutionary perspective, INHBE is relatively conserved in mammals, but its expression pattern differs from classical inhibin/activin family members. Unlike traditional members primarily expressed in gonads, INHBE exhibits significant transcriptional activity in metabolically active organs such as the liver and pancreas, suggesting roles beyond reproductive endocrine regulation, particularly in metabolic homeostasis.

Figure 1. Graphic representation of activin/INHBE signaling and interaction points with activin antagonists. (Deli A, et al., 2008)

Biological Significance

Recent research has highlighted a paradigm shift in understanding INHBE's biological significance. Once thought to play a peripheral role in reproductive hormone regulation, INHBE is now recognized as a key regulator of energy metabolism and stress responses. Traditionally, inhibins are known for suppressing pituitary follicle-stimulating hormone secretion, whereas activins exert the opposite stimulatory effect. For INHBE, accumulating evidence points to a central role in metabolism. Its expression is strongly induced under metabolic challenges, such as endoplasmic reticulum (ER) stress and fasting. During ER stress, INHBE upregulation via the unfolded protein response may serve as an adaptive mechanism to slow anabolic processes and promote cell survival. Remarkably, fasting induces a sharp increase in hepatic INHBE expression, acting as a "metabolic brake" to suppress potentially unnecessary cellular proliferation and growth in the liver and pancreas, thereby reallocating limited energy resources toward essential survival functions.

Cutting-edge genetic and pharmacological studies have further confirmed INHBE's critical role. Knockout models or neutralizing antibodies that inhibit INHBE function significantly ameliorate high-fat diet–induced metabolic disturbances, manifesting as reduced weight gain, alleviated hepatic steatosis, and improved insulin sensitivity. These findings strongly suggest that INHBE signaling contributes to the pathophysiology of obesity and related metabolic disorders. Its mechanisms may involve suppression of lipolysis, restriction of energy expenditure, or long-range modulation of white adipose tissue via hepatokine-mediated intercellular signaling. Therefore, INHBE is no longer viewed as a minor TGF-β family member but as a key signaling node activated under metabolic stress, coordinating systemic energy distribution and storage. In modern nutrient-rich environments, chronic activation may contribute to metabolic disease development.

Clinical Relevance

The clinical significance of INHBE is primarily focused on its potential as a therapeutic target for metabolic disorders. The global prevalence of non-alcoholic fatty liver disease, type 2 diabetes, and obesity underscores the need for novel treatment strategies beyond conventional therapies. Given INHBE's negative metabolic effects in preclinical models, inhibiting its activity represents an attractive therapeutic approach. Monoclonal antibodies or soluble receptor analogs targeting INHBE are being explored to neutralize the circulating protein or its signaling, thereby relieving its inhibitory effect on energy metabolism and promoting healthier metabolic phenotypes.

Genetic studies further support this potential. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms in the INHBE locus that correlate with lower waist-to-hip ratio and favorable body fat distribution, providing direct evidence of INHBE's role in human adipose biology. These findings not only validate preclinical models but also suggest that INHBE-based therapies may be especially effective in genetically predisposed patient populations.

Challenges remain in translating INHBE to the clinic. Precise elucidation of its molecular mechanisms, including specific receptors and downstream signaling pathways, is essential for developing highly specific drugs. A comprehensive assessment of potential long-term side effects is required, considering TGF-β family members' roles in tumorigenesis, immune regulation, and tissue repair. Although INHBE's direct effects on the reproductive system may be modest, careful evaluation is still warranted. Identifying reliable plasma INHBE levels as biomarkers is also critical for patient stratification and therapeutic monitoring. Overall, INHBE, a liver-derived signal activated by metabolic stress, opens new avenues for intervention in obesity-related complications, and its clinical development warrants close attention.

References

Bernard DJ, Chapman SC, Woodruff TK. Mechanisms of inhibin signal transduction. Recent Prog Horm Res. 2001;56:417-50.
Deli A, Kreidl E, Santifaller S, et al. Activins and activin antagonists in hepatocellular carcinoma. World J Gastroenterol. 2008 Mar 21;14(11):1699-709.

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