Lactylation-driven nuclear RIG-I promoted by lactate transporter inhibitor suppresses DNA damage repair through inhibiting PARP1 activity

RIG-I (DDX58) is typically localized in the cytoplasm and activates innate immunity. However, the mechanisms governing its nuclear translocation and functions remain incompletely understood. Here, we discover that RIG-I undergoes lactylation, which is mediated by the acetyltransferase PCAF. Treatment with the lactate transporter inhibitor syrosingopine blocks the efflux of lactate from cancer cells, increasing intracellular lactate concentration, promoting RIG-I lactylation, and enhancing the nuclear translocation of lactylated RIG-I in an importin 8-dependent manner. The nuclear-localized RIG-I interacts with PARP1 and attenuates its activity, thereby inhibiting DNA damage repair. Moreover, we find that low RIG-I expression is associated with unfavorable prognosis and survival in lung adenocarcinoma (LUAD). Syrosingopine treatment sensitizes LUAD cells to PARP inhibitor (PARPi) and potentiates the therapeutic efficacy of olaparib in a mouse LUAD model. Altogether, our study reveals that lactylation drives RIG-I nuclear function to inhibit DNA damage repair via PARP suppression. This supports the potential co-administration of syrosingopine and PARPi for LUAD treatment.