6PPD-Q exposure promotes hepatocellular carcinoma progression and confers resistance to ferroptosis.

Tire antioxidant degradation product N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6PPD-Q), an emerging environmental pollutant, has been suggested to influence tumor-related biological processes; however, its role in HCC remains unclear. Here, we evaluated the effects of 6PPD-Q on HCC cells by assessing transcriptomic profiles, proliferation, migration, and erastin-induced/Ferrostatin-1-inhibited ferroptosis, and interrogated the regulatory role of zinc finger X-linked duplicated family zinc finger C (ZXDC) using knockdown and overexpression approaches. 6PPD-Q markedly promoted HCC cell proliferation and migration while reducing sensitivity to erastin-triggered ferroptosis. Mechanistically, ZXDC expression was upregulated by 6PPD-Q in HCC cells and served as a prognostic indicator. Moreover, ZXDC acted as a critical mediator of these pro-tumorigenic and anti-ferroptotic effects: ZXDC knockdown attenuated 6PPD-Q-induced proliferation and migration while promoting ferroptosis, whereas ZXDC overexpression further suppressed ferroptosis. In parallel, multi-algorithm immune infiltration analyses showed that the 6PPD-Q-related gene risk score was significantly associated with multiple immune populations, with macrophage M0 cells showing a significant positive correlation with the risk score (R = 0.30, p < 0.001). Collectively, these findings identify a 6PPD-Q/ZXDC axis that links environmental exposure to HCC malignant progression and ferroptosis resistance, suggesting ZXDC as a potential biomarker and intervention target for HCC prevention and therapy.