Environmental benzophenone exposure promotes liver cancer cell proliferation via the IRE1α-XBP1s pathway

Humans are widely exposed to benzophenones, ultraviolet absorbers in sunscreens that accumulate in the liver. This study investigated the impact of chronic benzophenone exposure on hepatocellular carcinoma (HCC). We established a long-term culture model treating HepG2, Huh7 and normal hepatocyte LO2 with 5 nM 4-hydroxybenzophenone (4HBP), a major metabolite of benzophenones. Cell proliferation was evaluated using CCK-8 and colony formation assays in vitro, and tumor growth was assessed using a nude mouse xenograft model in vivo. Proteostasis, UPR activation, and the nuclear translocation of XBP1s were analyzed via Western blot and immunofluorescence. XBP1 was knocked down using siRNA, and the IRE1α-XBP1 pathway was inhibited with MKC8866. Interestingly, long-term 4HBP exposure significantly promoted HepG2 and Huh7 cell proliferation in vitro and accelerated the growth of HepG2 tumors in vivo, with minimal effects on LO2 cells. Mechanistically, 4HBP disturbed proteostasis and activated the IRE1α-XBP1s axis of the unfolded protein response (UPR) in HCC cells, which was critical for their increased aggressiveness. Collectively, these findings alert that environmental benzophenone exposure may increase the risk of HCC progression.