Activin E encoded by INHBE is mainly produced by the liver and regulates lipid storage and lipolysis through ALK7/ACVR1C in adipocytes. Reducing INHBE or ALK7 signaling can promote fat mobilization and alter fat distribution, making this liver–adipose tissue endocrine axis an emerging fat-loss target distinct from central appetite suppression.

Keywords: INHBE; Activin E; ALK7; ACVR1C; lipolysis; visceral fat; liver–adipose axis

1 Components of the INHBE/Activin E–ALK7 Signaling Axis

1.1 INHBE and Activin E

INHBE encodes the Inhibin βE subunit and belongs to the TGF-β superfamily. After the βE subunit forms Activin E, it can act as a liver-derived secreted factor involved in metabolic regulation. INHBE shows relatively prominent expression in the liver and can change in response to fatty acid load and nutritional status. Activin E can therefore transmit the lipid status sensed by the liver to adipose tissue and serves as an important Hepatokine linking hepatic lipid load with the energy-storage state of adipocytes.

1.2 ALK7/ACVR1C

ALK7 is encoded by ACVR1C and belongs to the type I serine/threonine kinase receptor family of the TGF-β superfamily. It has important metabolic functions in mature adipocytes. Activin E can activate SMAD2/3 signaling through ALK7, making ACVR1C a key receptor node through which liver-derived Activin E regulates adipocyte lipid metabolism. Here, ALK7 refers to Activin receptor-like kinase 7 and belongs to a different receptor system from Anaplastic lymphoma kinase (ALK).

1.3 Activin E Receptor Complex

(1) ActRIIA/ActRIIB Participate in Receptor Assembly

Activin E requires type II Activin receptors for signal transduction, and ActRIIA and ActRIIB can serve as components of the receptor complex. After the ligand binds the type II receptor, ALK7 recruitment is promoted, allowing the type II and type I receptors to form a signaling-competent complex.

(2) ALK7 Determines Adipocyte Signal Output

The type II receptor phosphorylates ALK7 through its intracellular kinase activity, and activated ALK7 further acts on SMAD2/3. ActRIIA/ActRIIB represent a receptor level shared by multiple Activin-family ligands, whereas ALK7 more directly determines the functional output of Activin E in adipocytes. Therefore, research on this signaling axis mainly focuses on fat storage, lipolysis, and lipid distribution.

2 Activin E–ALK7–SMAD2/3 Signaling Mechanism

2.1 SMAD2/3 Activation

After Activin E induces formation of a complex between type II receptors and ALK7, ALK7 promotes phosphorylation of SMAD2 and SMAD3. p-SMAD2/3 then forms a complex with SMAD4 and enters the nucleus, where it regulates expression of genes related to adipocyte metabolism. ALK7-SMAD2/3 therefore constitutes the classical signaling axis through which Activin E regulates adipose tissue function.

2.2 PPARG-Related Transcriptional Regulation

Activin E–ALK7 signaling can affect PPARG and the mature adipocyte metabolic program it controls. PPARG not only participates in Adipogenesis but also maintains the capacity of mature adipocytes for lipid uptake, storage, and mobilization. Therefore, changes in ALK7 signaling do not merely alter a single lipolytic enzyme but adjust the overall lipid-storage and lipid-utilization state of adipocytes.

2.3 Inhibition of Lipolysis

Mobilization of adipocyte Triglyceride mainly depends on the coordinated actions of ATGL/PNPLA2, HSL/LIPE, and lipid droplet-associated proteins. Catecholamines can promote lipolysis through the β-Adrenergic receptor–cAMP–PKA system, whereas Activin E–ALK7–SMAD2/3 provides a relatively inhibitory input that reduces adipocyte responsiveness to lipolytic stimulation, making Triglyceride more likely to remain within lipid droplets. When INHBE or ALK7 is reduced, this inhibitory effect is weakened and FFA and Glycerol release increase.

3 Metabolic Feedback Between the Liver and Adipose Tissue

3.1 Hepatic Fatty Acid Sensing

After FFA generated by adipose tissue lipolysis enters the circulation, part of it is taken up by the liver. Hepatocytes can regulate INHBE expression and Activin E output according to fatty acid load, allowing the liver not only to process fatty acids but also to feed back signals regulating fat storage and lipolysis to adipose tissue according to its own lipid burden.

3.2 Activin E Restricts Adipose Tissue Lipolysis

After circulating Activin E acts on ALK7 in adipocytes, SMAD2/3 signaling is enhanced and continued large-scale release of FFA from adipocytes is restricted. This feedback can be summarized as “increased adipose tissue FFA release—increased hepatic fatty acid load—increased INHBE/Activin E—ALK7 activation—restriction of lipolysis,” thereby forming a negative-feedback mechanism against sustained fatty acid influx.

3.3 Nutritional Status and Fat Storage

During fasting or nutrient insufficiency, moderate restriction of lipolysis helps prevent excessively rapid depletion of fat stores and excessive increases in circulating FFA. During chronic energy excess, sustained Activin E–ALK7 input may maintain a stronger fat-storage tendency in adipocytes. This signaling axis is clearly dependent on nutritional status, and its physiological homeostatic role needs to be distinguished from its effects on fat accumulation under obesity-related conditions.

4 Fat-Loss Mechanisms After Reduction of INHBE/ALK7

4.1 Reduction of INHBE

Reducing INHBE expression in hepatocytes can decrease Activin E production, thereby lowering ALK7 activation signals received by adipocytes. As the inhibitory SMAD2/3 input weakens, Triglyceride is more readily converted into FFA and Glycerol and released from lipid droplets, thereby reducing long-term storage in adipose tissue. This strategy acts at the production end of the liver-derived ligand and essentially weakens the fat-storage signal transmitted from the liver to adipose tissue.

4.2 Reduction of ALK7/ACVR1C

Reducing ACVR1C expression in adipose tissue can directly decrease ALK7 and lower adipocyte responsiveness to Activin E. Unlike INHBE reduction, this strategy does not directly alter circulating Activin E but relieves inhibition of lipolysis at the receptor level. Because ALK7 can also receive signals from other related ligands, the pharmacological coverage of ALK7 knockdown and INHBE knockdown is not completely identical.

4.3 Visceral Fat and Body Composition

Human genetic signals related to INHBE and ACVR1C more prominently point toward waist-to-hip ratio, visceral fat, and fat distribution rather than only overall Body Weight. This suggests that the pathway is more appropriately evaluated from the perspectives of Fat Distribution and Body Composition, with particular distinction among changes in Visceral Fat, Subcutaneous Fat, Liver Fat, and Lean Mass.

Table 1 Characteristics of Different Intervention Levels Targeting INHBE and ALK7

5 Lipid Fate After Fat Loss

5.1 Fat-Mass Reduction and Lipid Mobilization

After the inhibitory effect of ALK7 on lipolysis is relieved, Triglyceride in adipocytes is broken down into FFA and Glycerol, but a reduction in adipose tissue does not mean that these lipids have been completely consumed by the body. Released FFA still needs to enter skeletal muscle, liver, and other tissues for further oxidation or reprocessing. Therefore, the key to INHBE/ALK7 intervention lies not only in increasing Lipolysis but also in subsequent fatty acid utilization and tissue distribution.

5.2 Redistribution of FFA and Hepatic Lipids

When lipolysis is markedly enhanced but peripheral fatty acid oxidation capacity is insufficient, large amounts of FFA can enter the liver and be re-esterified into Triglyceride, causing redistribution of lipids from adipose tissue to the liver. In some models, INHBE deficiency can simultaneously produce reduced Fat Mass and increased hepatic lipid, indicating that “reduced adipose tissue storage” and “reduced ectopic lipid deposition” do not necessarily occur simultaneously.

5.3 Evaluation of Complete Metabolic Benefit

Determining whether INHBE/ALK7 intervention truly improves metabolism requires simultaneous evaluation of Visceral Fat, Subcutaneous Fat, Liver Fat, circulating FFA, Triglyceride, Glucose, and Insulin status. If Fat Mass decreases while persistent FFA elevation or hepatic Triglyceride accumulation occurs, this suggests that lipids may have been redistributed rather than adequately oxidized and utilized.

6 Human Genetic Evidence for INHBE and ACVR1C

6.1 Reduced INHBE Function

Predicted loss-of-function variants in INHBE are associated with a lower BMI-adjusted waist-to-hip ratio and a more favorable abdominal fat distribution, together with improvement in some metabolic risk indicators. The phenotype is not simply equivalent to a marked decrease in BMI, suggesting that INHBE is more likely to influence the location of adipose tissue storage and fat distribution rather than independently determining overall body weight.

6.2 Reduced ACVR1C Function

Partial loss-of-function variants in ACVR1C are likewise associated with a lower waist-to-hip ratio and a more favorable fat distribution. INHBE and ACVR1C are located at the ligand and receptor ends, respectively, and genetic variants at both ends produce similarly directed body-fat-distribution phenotypes, providing mutually supportive evidence that Activin E–ALK7 participates in regulation of human fat storage.

6.3 Boundaries of Genetic Evidence Interpretation

Lifelong carriage of loss-of-function variants is not completely equivalent to pharmacological knockdown using RNAi in adulthood. Intervention timing, degree of target reduction, tissue specificity, and long-term compensation can all alter the final phenotype. Therefore, genetic evidence is more suitable for validating target direction and potential safety windows and cannot directly predict how much Body Weight or Fat Mass reduction a drug can produce.

7 Representative Investigational Drugs Targeting INHBE/ALK7

7.1 ARO-INHBE

(1) Drug Design and Target

ARO-INHBE is an RNA interference (RNAi) candidate targeting INHBE. It reduces INHBE expression and Activin E output by lowering INHBE mRNA levels in hepatocytes. Because INHBE is mainly produced in the liver, ARO-INHBE weakens INHBE/Activin E–ALK7 signaling from the liver-derived ligand side rather than acting directly on ALK7 in adipocytes.

(2) Fat-Loss Mechanism

After INHBE reduction, circulating Activin E input decreases, adipocyte ALK7-SMAD2/3 signaling is correspondingly weakened, and inhibition of lipolysis is partially relieved, allowing Triglyceride within lipid droplets to be more readily mobilized into FFA and Glycerol. Its main pharmacological direction is not direct suppression of Food Intake but alteration of the storage–mobilization balance in adipose tissue. Therefore, Visceral Fat, Total Fat, and Liver Fat better reflect its characteristics than Body Weight alone.

(3) Clinical Research Characteristics

ARO-INHBE has entered early-stage human studies, with both monotherapy and combination with Tirzepatide being explored. Current research focuses include the degree of Activin E reduction, Visceral Fat, Total Fat, Liver Fat, and Body Composition changes. Early results have shown signals of fat loss and improvement in hepatic fat, but long-term efficacy, lipid disposition, and metabolic safety still require further validation.

7.2 ARO-ALK7

(1) Drug Design and Target

ARO-ALK7 is also an RNAi candidate, but it directly targets ACVR1C mRNA to reduce ALK7 expression in adipose tissue. Unlike ARO-INHBE, which reduces Activin E from the liver, ARO-ALK7 acts directly at the receptor end of the liver–adipose axis, reducing corresponding signal output even when adipocytes remain exposed to Activin E because ALK7 expression is decreased.

(2) Fat-Loss Mechanism

After ALK7 reduction, the ability of Activin E and other related ligands to activate SMAD2/3 decreases, weakening inhibition of lipolysis in adipocytes and thereby increasing lipid mobilization while limiting sustained fat storage and adipocyte hypertrophy. Because ALK7 does not receive signals exclusively from Activin E, ARO-ALK7 can theoretically affect a broader range of ALK7-related signaling, so its pharmacological effects are not completely equivalent to INHBE knockdown.

(3) Clinical Research Characteristics

ARO-ALK7 has entered Phase 1/2a clinical development. Interim data have demonstrated substantial knockdown of adipose ALK7 mRNA together with a reduction in Visceral Fat. Further studies are still required to determine its long-term effects on Fat Mass, Liver Fat, and overall Body Composition and whether favorable lipid distribution can be sustained.

7.3 Pharmacological Differences Between ARO-INHBE and ARO-ALK7

(1) Ligand End and Receptor End

ARO-INHBE reduces hepatic Activin E production and represents ligand-level intervention, whereas ARO-ALK7 reduces ALK7 in adipocytes and represents receptor-level intervention. The former focuses more specifically on INHBE/Activin E itself, while the latter can simultaneously weaken signaling from multiple upstream ligands that use ALK7. Therefore, the two RNAi strategies are not completely equivalent upstream and downstream alternatives.

(2) Differences in Tissue Targeting

ARO-INHBE mainly achieves RNAi silencing in the liver and indirectly alters adipose tissue by reducing circulating Activin E, whereas ARO-ALK7 needs to directly reduce ACVR1C expression in adipose tissue. The two therefore represent two RNAi pharmacological approaches: targeting a liver-derived Hepatokine and targeting an adipose tissue receptor.

(3) Differences in Evaluation Focus

ARO-INHBE is more appropriately evaluated by combining Activin E, Visceral Fat, and Liver Fat to assess the liver–adipose endocrine axis, whereas ARO-ALK7 requires greater attention to adipose tissue ACVR1C, p-SMAD2/3, and changes in lipolysis. Both strategies should ultimately be evaluated together with Fat Mass, Lean Mass, Liver Fat, and circulating FFA to determine the quality of fat loss.

Table 2 Comparison of the Pharmacological Characteristics of ARO-INHBE and ARO-ALK7

7.4 Combination Strategy With Tirzepatide

(1) Complementary Mechanisms of Action

Tirzepatide reduces Energy Intake and improves glucose metabolism through GIPR- and GLP-1R-related mechanisms, whereas ARO-INHBE and ARO-ALK7 mainly alter the storage and mobilization state of adipose tissue. These two pharmacological approaches act at the energy-intake side and fat-storage side, respectively, so their combination does not simply duplicate enhancement of the same appetite-suppression pathway.

(2) ARO-INHBE Combined With Tirzepatide

The combination of ARO-INHBE with Tirzepatide mainly tests whether further relief of Activin E-mediated fat-storage signaling on the basis of reduced food intake can increase improvements in Visceral Fat, Total Fat, and Liver Fat. The key question is whether the proportion of Fat Mass in total weight loss increases and whether stronger lipid mobilization can simultaneously maintain favorable Lean Mass and hepatic fat status.

(3) ARO-ALK7 Combined With Tirzepatide

The combination of ARO-ALK7 with Tirzepatide relieves inhibition of lipolysis from the adipose tissue receptor side while adding GIPR/GLP-1R-mediated reduction in energy intake. Evaluation focuses include Visceral Fat, Fat Mass, Liver Fat, and Lean Mass to determine whether enhanced fat loss can produce a more favorable body composition rather than merely increasing Body Weight reduction.

8 Key Experiments in INHBE/Activin E–ALK7 Research

8.1 Target and SMAD Signaling

At the INHBE end, hepatic INHBE expression and Activin E output should be monitored, whereas at the ALK7 end, ACVR1C expression in adipose tissue should be the main focus, together with p-SMAD2/3 to confirm whether classical receptor signaling changes in the expected direction after intervention. ActRIIA/ActRIIB- and ALK7-related tools can be used to determine the dependence of Activin E on the complete type II/type I receptor complex. ALK4/ALK5/ALK7 inhibitors such as SB431542 can assist in deconvoluting SMAD2/3 signaling but cannot serve as the sole evidence for ALK7 specificity.

8.2 Lipolysis and Lipid Droplet Phenotypes

Lipolytic function can be directly evaluated through Glycerol and FFA release and combined with ATGL/PNPLA2, HSL/LIPE, PLIN1, and related indicators to analyze the lipolytic program. TG content and lipid droplet area reflect the lipid-storage state of adipocytes. Therefore, “increased lipolytic products + reduced TG or lipid droplets” provides stronger evidence of the actual effect of Activin E–ALK7 on lipid mobilization than observation of changes in a single protein alone.

8.3 Body Composition and Hepatic Fat

In vivo studies should separately evaluate Body Weight, Total Fat, Visceral Fat, Subcutaneous Fat, Lean Mass, and Liver Fat while simultaneously monitoring circulating FFA, TG, Glucose, and Insulin. INHBE/ALK7 intervention particularly requires attention to whether persistent FFA elevation or increased hepatic fat occurs after Fat Mass reduction, so that effective lipid utilization can be distinguished from simple lipid redistribution.

9 Research Products Related to INHBE/Activin E–ALK7

9.1 Activin Receptors and ALK7-SMAD Signaling Research

9.2 Evaluation of Adipocyte Lipid Storage and Lipolytic Function

9.3 Liver–Adipose Axis and Fat-Loss Mechanism Controls

INHBE/Activin E–ALK7 connects hepatic fatty acid sensing with adipose tissue energy storage and restricts lipolysis. ARO-INHBE and ARO-ALK7 validate the pharmacological potential of this signaling axis from the ligand and receptor ends, respectively. Their research value lies not only in reducing Fat Mass but also in improving visceral fat, hepatic fat, and overall lipid distribution, while providing a new complementary mechanism for combination with food-intake-targeting weight-loss drugs such as Tirzepatide.

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