INHBA Protein Fuels Colorectal Cancer by Hijacking Immunity and Blocking Cell Death
A new study reveals how INHBA overexpression drives colorectal cancer by shielding tumor cells from ferroptosis and reprogramming immune cells.
Summary
Researchers at Central South University identified Inhibin beta A (INHBA) as a key driver of colorectal cancer (CRC) progression. Elevated INHBA expression correlates with worse survival in CRC patients. Mechanistically, INHBA stabilizes the mitochondrial transporter SLC25A10 by blocking its ubiquitin-mediated degradation via TRIM21. This stabilization enables tumor cells to export succinate, which binds the SUCNR1 receptor on macrophages, converting them to immune-suppressive M2 tumor-associated macrophages. Simultaneously, SLC25A10 shuttles glutathione into mitochondria, activating the mtGSH/GPX4 axis and suppressing ferroptosis. Together these dual mechanisms accelerate CRC growth and metastasis, positioning INHBA and its downstream effectors as promising therapeutic targets.
Detailed Summary
Colorectal cancer (CRC) remains the third leading cause of cancer death globally, and its molecular underpinnings—particularly in the tumor microenvironment (TME) and cell-death regulation—are incompletely understood. This study sought to characterize the oncogenic role of Inhibin beta A (INHBA), a TGF-β superfamily member, across both immunological and metabolic dimensions of CRC progression.
Using multi-database bioinformatics (TCGA, GEO), human colon tissue microarrays (96 CRC and 74 normal tissues), and Kaplan–Meier survival analysis, the authors confirmed that INHBA is significantly overexpressed in CRC and independently predicts shortened overall and disease-free survival. AUC values for 1-, 3-, and 5-year OS prediction reached 0.798, 0.717, and 0.742, respectively. Cox regression confirmed INHBA as an independent prognostic factor.
In vitro experiments in HCT116 and LoVo CRC cell lines, and in vivo syngeneic subcutaneous tumor models in C57BL/6 mice using MC38 cells, demonstrated that INHBA overexpression accelerates proliferation, migration, and invasion, while knockdown suppresses these behaviors. EMT marker profiling confirmed INHBA promotes the epithelial-to-mesenchymal transition.
Mechanistically, INHBA acts as a scaffold protein that physically interacts with both SLC25A10 (a mitochondrial dicarboxylate carrier) and the E3 ubiquitin ligase TRIM21. By bridging these proteins, INHBA prevents TRIM21 from executing K48-linked polyubiquitination and proteasomal degradation of SLC25A10, thereby stabilizing SLC25A10 protein levels. The elevated SLC25A10 then drives two distinct pro-tumorigenic pathways: (1) it transports succinate from the mitochondrial matrix to the cytoplasm and extracellular space, where secreted succinate binds SUCNR1 (GPR91) on tumor-associated macrophages (TAMs), promoting their polarization toward the immunosuppressive M2 phenotype; and (2) it imports cytoplasmic glutathione (GSH) into the mitochondria, activating the mtGSH/GPX4 axis and suppressing mitochondria-dependent ferroptosis in CRC cells.
These findings establish INHBA as a multifunctional oncogenic hub in CRC, simultaneously remodeling immune surveillance and blocking iron-dependent cell death. The identification of the INHBA–TRIM21–SLC25A10 axis provides a mechanistic framework for developing INHBA-targeted inhibitors or combination immunoferroptosis strategies, which could represent a novel therapeutic avenue for CRC patients with high INHBA expression.
Key Findings
- INHBA is overexpressed in CRC and independently predicts poor overall and disease-free survival (AUC up to 0.798).
- INHBA acts as a scaffold blocking TRIM21-mediated K48-ubiquitination of SLC25A10, stabilizing the mitochondrial transporter.
- Elevated SLC25A10 exports succinate extracellularly, activating SUCNR1 on macrophages and driving immunosuppressive M2 polarization.
- SLC25A10 also imports GSH into mitochondria, activating mtGSH/GPX4 and suppressing mitochondria-dependent ferroptosis in CRC cells.
- INHBA knockdown reduces tumor growth, invasion, and M2 macrophage infiltration in syngeneic mouse models.
Methodology
The study combined multi-cohort bioinformatics (TCGA, GEO, GEPIA), human colon tissue microarrays, in vitro gain/loss-of-function experiments in CRC cell lines, and in vivo syngeneic subcutaneous tumor models in C57BL/6 mice. Mechanistic dissection employed co-immunoprecipitation, ubiquitination assays, metabolite profiling, and immune cell polarization assays.
Study Limitations
All in vivo experiments used syngeneic mouse models rather than patient-derived xenografts, which may not fully recapitulate human CRC heterogeneity. The causal directionality of the INHBA–TRIM21–SLC25A10 interaction in clinical tumor samples was not directly validated. Long-term therapeutic efficacy and safety of INHBA inhibition were not assessed.
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