P4HB, a novel succinated protein, is essential for fumarate-induced cancer metastasis.

Fumarate hydratase (FH) catalyzes the conversion of fumarate to malate in the tricarboxylic acid cycle. Its deficiency leads to fumarate accumulation, which is associated with kidney cancer metastasis, though the exact mechanisms remain unclear. Here, we identify prolyl 4-hydroxylase beta (P4HB) as a novel fumarate target in FH-deficient cancer cells that promotes migration and invasion. FH knockdown in human renal cancer cells significantly enhanced migratory and invasive capacities by 10- and 8-fold, respectively. Mechanistically, fumarate-induced succination stabilizes P4HB, promoting type I collagen production and enhancing tumor metastasis. P4HB knockdown markedly suppresses FH deficiency-induced metastasis in xenograft models. Fluorescence intensity in the FH knockdown group was about 10-fold higher, and tumor-bearing liver weight was approximately 1.5-fold greater than that in the FH and P4HB co-knockdown group. These results underscore the pivotal role of P4HB in metastasis. Additionally, we reveal NDP52 as a specific autophagy receptor that recognizes and binds to P4HB, mediating its degradation through the autophagy-lysosome pathway. However, succination of P4HB disrupts this recognition, interaction, and degradation, stabilizing P4HB. Together, these findings provide new insights into how fumarate-mediated succination affects P4HB protein stability and cancer metastasis, and suggest that P4HB could serve as a potential therapeutic target in FH-deficient cancers.