SLC25A1 regulates glycolysis via ALDOC global histone H3 acetylation to promote cutaneous squamous cell carcinoma development

Metabolic reprogramming is a hallmark of cutaneous squamous cell carcinoma (cSCC), yet the underlying mechanisms remain incompletely understood. SLC25A1, a mitochondrial citrate transporter, has been implicated in tumor progression, but its role in cSCC is unclear. This study aimed to investigate the role of SLC25A1 in cSCC progression and elucidate the underlying molecular mechanisms. SLC25A1 expression was examined in cSCC tissues and cell lines using immunohistochemistry, RT-qPCR, and Western blotting. Functional assays, including proliferation, apoptosis, migration, and invasion analyses, were performed following SLC25A1 knockdown or overexpression. RNA sequencing and metabolic assays were conducted to explore underlying mechanisms. Chromatin immunoprecipitation (ChIP)-qPCR was used to assess pan-histone H3 acetylation. In vivo effects were evaluated using DMBA/TPA-induced cSCC mouse models, with pharmacological inhibition by CTPI-2. SLC25A1 was significantly upregulated in cSCC and promoted tumor cell proliferation, migration, and invasion while inhibiting apoptosis. Mechanistically, SLC25A1 enhanced glycolysis by increasing pan-histone H3 acetylation at the ALDOC promoter, thereby upregulating ALDOC expression. Knockdown of SLC25A1 reduced glycolytic activity and tumor growth, whereas ALDOC overexpression partially rescued these effects. Pharmacological inhibition of SLC25A1 with CTPI-2 suppressed tumor progression and altered metabolic profiles in vivo. SLC25A1 promotes cSCC progression by regulating glycolysis through pan-acetylated H3-mediated transcriptional activation of ALDOC. Targeting SLC25A1 may represent a promising therapeutic strategy for cSCC.