Colorectal cancer (CRC) progression remains a major clinical challenge, emphasizing the need to uncover regulatory mechanisms. Succinyl-CoA ligase GDP-forming subunit beta (SUCLG2), a mitochondrial enzyme in the tricarboxylic acid cycle, is implicated in various cellular processes, but its role in CRC is not well understood.

SUCLG2 was identified through integrated bioinformatics analysis of CRC datasets, followed by multi-omics clinical validation. Its function was assessed via in vitro and in vivo assays, and mechanisms were explored using transcriptomic, metabolomic, and epigenetic approaches.

SUCLG2 expression was significantly downregulated in CRC, correlating tightly with advanced TNM stage and poor prognosis. Functional assays demonstrated that SUCLG2 restricts CRC cell proliferation and xenograft tumor growth. Mechanistically, SUCLG2 reactivated GADD45G transcription through S-adenosylmethionine (SAM)-dependent epigenetic remodeling, reducing intracellular SAM levels, suppressing DNA methyltransferase (DNMT) activity, and alleviating GADD45G promoter hypermethylation. GADD45G was established as a critical downstream mediator of the SUCLG2/p53 signaling axis, as its knockdown abrogated the tumor-suppressive effects of SUCLG2. Clinical validation confirmed a robust positive correlation between SUCLG2 and GADD45G expression, alongside a negative correlation with GADD45G promoter methylation in CRC patients.

Our findings establish SUCLG2 as a tumor suppressor that acts via a SAM‑DNMT epigenetic axis to demethylate GADD45G and reactivate p53‑mediated growth inhibition, highlighting SUCLG2 as a promising prognostic biomarker and therapeutic target for CRC.