PARK7-driven IGF2BP3–K76 lactylation mediates ferroptosis and HAIC resistance in hepatocellular carcinoma

Oxaliplatin/5-fluorouracil (OXA/5-FU)-based hepatic artery infusion chemotherapy (HAIC) represents a promising strategy against advanced hepatocellular carcinoma (HCC), yet acquired resistance frequently impedes its efficacy. Here, we identify lactylation of IGF2BP3 at lysine 76 (IGF2BP3-K76lac) as a key driver of HAIC resistance. IGF2BP3-K76lac overexpression enhances chemoresistance in vitro and in vivo. Mechanistically, lactylation at IGF2BP3 K76 strengthens its affinity for m6A-modified FSP1 mRNA, upregulating FSP1 and conferring ferroptosis resistance. Blocking of IGF2BP3-K76lac bolsters OXA/5-FU-induced ferroptosis, disrupts antioxidant defenses, and curbs tumor growth. Moreover, PARK7 functions as a lactyltransferase to facilitate IGF2BP3-K76lac via increasing the binding of lactate at IGF2BP3-K76 site. Finally, blocking antibody targeting IGF2BP3-K76lac was shown to work synergistically with OXA/5-FU to restore chemosensitivity. Taken together, our findings reveal a critical role for the PARK7-IGF2BP3-K76lac-FSP1 axis in HAIC resistance, highlighting IGF2BP3-K76lac as a potential therapeutic target in HCC.