Inhibition of SLC25A10 promotes cellular senescence and impedes hepatocellular carcinoma progression.

Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality with limited therapeutic options. Solute carrier family 25 member 10 (SLC25A10), a mitochondrial transporter linked to metabolic regulation and tumor progression, has unclear roles in HCC pathogenesis. This study aimed to elucidate the functional and mechanistic contributions of SLC25A10 to HCC development.

Methods: The International Cancer Genome Consortium (ICGC) database, GAO et al. dataset, quantitative real-time polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry (IHC) staining were used to explore the expression levels of SLC25A10 in HCC tissues and cell lines. Functional assays [cell counting kit-8, colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, SA-β-galactosidase staining, and flow cytometry] and a subcutaneous xenograft mouse model were employed to assess the effects of SLC25A10 knockdown on proliferation, senescence, and tumorigenesis. Finally, NecroX-7, a high mobility group box 1 (HMGB1) inhibitor, was used to delineate the underlying molecular mechanisms involved in cell senescence caused by SLC25A10 knockdown.

Results: The protein and messenger RNA (mRNA) levels of SLC25A10 in HCC tissues were higher than those in adjacent normal tissues. Knockdown of SLC25A10 suppressed cell proliferation, induced senescence-associated β-galactosidase activity, and triggered G1 phase arrest by downregulating cyclin-dependent kinase 4 (CDK4)/Cyclin D1 and upregulating cyclin-dependent kinase inhibitor 2A (CDKN2A). In vivo, SLC25A10 silencing reduced tumor growth and decreased KI67/proliferating cell nuclear antigen (PCNA) expression, while enhancing HMGB1, a senescence-associated secretory phenotype (SASP) marker. Mechanically, pharmacological inhibition of HMGB1 with NecroX-7 partially reversed the anti-proliferative and pro-senescent effects of SLC25A10 knockdown, restoring cell cycle progression.

Conclusions: SLC25A10 promotes HCC progression by suppressing cellular senescence. Pharmacological or genetic inhibition of SLC25A10 triggers tumor suppression through HMGB1-mediated SASP signaling, positioning SLC25A10 as a promising therapeutic target for HCC intervention.