Fumarate reprograms the ubiquitinated proteome to confer ferroptosis resistance in clear cell renal cell carcinoma

ABSTRACT:

Clear cell renal cell carcinoma (ccRCC) is a kidney malignancy characterized by aberrant lipid accumulation and is intrinsically sensitive to ferroptosis. However, the mechanisms by which ccRCC escapes ferroptotic vulnerability remain poorly understood. Here, we report that fumarate hydratase (FH) deficiency drives fumarate accumulation, which induces extensive remodeling of the ubiquitinated proteome and confers increased resistance to ferroptosis in ccRCC. Mechanistically, fumarate-mediated C706 succination of ubiquitin-like modifier-activating enzyme 1 (UBA1), the primary E1 activating enzyme, significantly impairs its interaction with ubiquitin-conjugating enzyme E2 G2 (UBE2G2), concomitant with a global reduction of ubiquitination. Specifically, diminished ubiquitination increases the protein levels of activating transcription factor 4 (ATF4) and elevates SLC7A11 expression, thereby inhibiting ferroptosis. Importantly, a designed cell-penetrating peptide attenuates fumarate-induced UBA1 succination, suppresses the ATF4-SLC7A11 axis, and enhances ferroptosis sensitivity of ccRCC. Collectively, these findings reveal that FH deficiency drives ubiquitinome dysregulation and suppresses ferroptosis, thereby linking ubiquitinated proteome reprogramming to tumor progression and unveiling potential therapeutic targets and strategies for treating ccRCC.

INSTRUMENT(S): Liquid Chromatography MS - negative - reversed-phase-c30, Liquid Chromatography MS - positive - reversed-phase-c30

PROVIDER: MTBLS15364 | MetaboLights | 2026-10-16

REPOSITORIES: MetaboLights