Novel Perfluoroalkyl Substance GenX exposure promotes non-small cell lung cancer progression by regulating the OTUB1/STAT3/VEGF axis.

Lung cancer continues to be one of the deadliest malignancies worldwide, and its pathological progression is closely linked to a wide spectrum of environmental risk factors. Hexafluoropropylene oxide dimer acid (HFPO-DA), an emerging class of per- and polyfluoroalkyl substances (PFAS), has been extensively detected in global aquatic environments and biological samples in recent years. However, its potential role in lung cancer development and the underlying molecular events remain largely unexplored. In this work, we uncovered that HFPO-DA exposure notably boosted the growth, colony formation, and invasive capacity of human non-small cell lung cancer (NSCLC) celllines A549 and H1975. At the mechanistic level, HFPO-DA elevated the expression level of the deubiquitinatingenzyme OTUB1,reinforced the physical association between OTUB1 and STAT3, suppressed the ubiquitination-dependent breakdown of STAT3, and ultimately promoted STAT3 phosphorylation and functional activation. Upon translocation into the nucleus, activated STAT3 boosted the transcription of VEGF, strengthened VEGF autocrine signaling,and further triggered the VEGFR2 pathway through paracrine action, forming a self-reinforcing feedback loop.In vivo assays further confirmed that HFPO-DA administration (1, 5, 10 mg/kg/day) dose-dependentlyaccelerated the growth of subcutaneous tumor xenografts in nude mice, accompaniedby markedly elevated VEGF expression andVEGFR2 phosphorylation within tumor tissues. Collectively, our findings uncover a previously unrecognized molecular cascade by which HFPO-DA drives NSCLC progression via the OTUB1/STAT3/VEGF signaling axis. These resultsoffer key theoretical support for assessing the health risks posed by emerging PFAScontaminants and provide innovative directions for environmental etiology research and intervention development in lung cancer.