Liu Xinyi,Du Wenqian,Wang Jingfei,Yin Tingyi,He Ke,Zhang Zhengyi,Liu Meng,Gan Xinyi,Cheng Baochen,Luo Ruiting,Zheng Yan
Background 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. Objective This study aimed to investigate the role of SLC25A1 in cSCC progression and elucidate the underlying molecular mechanisms. Methods 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. Results 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. Conclusions 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. Graphical
Non-histone proteins localized in membrane, cytosol and nucleus are lactylated to promote tumor progression. However, whether mitochondrial proteins undergo lactylation and contribute to tumor progression remains unexplored. Here, we identified multiple lactylated mitochondrial proteins in human renal cell carcinoma (RCC) cells using lactylome profiling. Among these, malate dehydrogenase 2 (MDH2)–the only lactylated protein in the tricarboxylic acid (TCA) cycle–emerged as a key target, with K239 as its lactylation site. MDH2 K239la levels are regulated by KAT8 and SIRT3. Under low-glucose, high-lactate conditions mimicking the tumor microenvironment, MDH2 K239la elevated the NADH/NAD + ratio to drive ATP production and boosted NADPH generation to reduce ROS. This enables cells to alleviate oxidative stress, sustain mitochondrial function, and promote RCC malignancy in vitro and in vivo . Mechanistically, MDH2 K239la enhances MDH2 enzymatic activity and strengthens its interaction with the citrate transporter SLC25A1. This facilitates citrate efflux, fueling IDH1-dependent NADPH production when lactate serves as an energy source. Collectively, we unveil a lactylation-dependent mechanism that reprograms mitochondrial metabolism to confer oxidative stress resistance and drive RCC progression. Targeting mitochondrial proteins lactylation, exemplified by MDH2 K239la , represents a promising therapeutic strategy for RCC.
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