Glucose starvation induces fumarate hydratase succinylation and inhibits ferroptosis to maintain colon cancer cell proliferation.

Cancer cells frequently reside in a glucose-deprived microenvironment due to rapid tumor proliferation and insufficient angiogenesis. However, the mechanisms by which colorectal cancer cells (CRC) adapt to glucose starvation to sustain proliferation remain unclear. Succinylation, a novel post-translational modification, has been implicated in regulating tumor cell proliferation and survival under nutrient stress. Our study reveals that fumarate hydratase (FH), a key enzyme in the tricarboxylic acid (TCA) cycle, is downregulated in CRC and acts as a tumor suppressor. Under glucose starvation mimicked in vitro, FH protein expression is reduced, leading to abnormal accumulation of its upstream metabolites fumarate and succinate, which correlates with advanced clinical stage and poor prognosis in CRC patients. Mechanistically, accumulated fumarate specifically binds to and stabilizes the NRF2 protein, upregulating the expression of GPX4 and FTH1 to inhibit ferroptosis, thereby sustaining CRC cell proliferation. Meanwhile, glucose starvation induces CPT1A-mediated succinylation of FH at residues K66/K80, reducing FH protein stability and promoting its degradation via the autophagy-lysosome pathway. Our findings reveal the critical role of FH and its succinylation in CRC cell adaptation to glucose starvation, inhibiting ferroptosis, and maintaining cancer cell proliferation, providing novel potential targets and a theoretical basis for the clinical treatment of CRC.