Formaldehyde Promoted Tumor Cell Growth Through Reinforced Lactylation of Poly (ADP‐Ribose) Polymerase 1

ABSTRACT As a group I carcinogen, environmental exposures to formaldehyde (FA) have been associated with various types of malignancies. However, exact mechanisms of FA‐triggered carcinogenesis are still not clear. Lactylation is recently identified as a post‐translational modification driven by overproduced lactic acid (LA) that regulates protein activities in different cellular processes. Our previous studies clearly demonstrated that environmentally relevant levels of FA could elevate LA in tumor cells. Poly (ADP‐ribose) polymerase 1 (PARP1) is a major player in DNA repair and tumor cell survival, which has been shown to be activated by lactylation. In order to examine if PARP1 lactylation is promoted by FA environmental exposure, subcutaneous tumor models were established using BALB/c nude mice, which were exposed to 2.0 mg/m 3 FA for 14 days. FA significantly elevated LA concentrations ( p = 0.011) in the tumor tissues, which was confirmed in A549 cells treated with 100 μM FA in vitro. Both activity and lactylation of PARP1 were found to be induced by FA, which also enhanced DNA repair and tumor‐promotive functions in vitro. Inhibition of LA production through lactate dehydrogenase A (LDHA) knockout reduced FA‐potentiated PARP1 lactylation and activity. Collectively, these results revealed for the first time that FA promoted tumor cell growth through enhanced PARP1 lactylation, which could be the underlying mechanism of FA‐related carcinogenesis.