Abstract

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants linked to diabetes, yet their role in diabetic complications is poorly understood. This study demonstrates that exposure to multiple PFAS subtypes significantly delays wound healing in diabetic rats. Through integrated transcriptomic and network toxicology approaches, we identified heat shock protein 90 beta family member 1 (HSP90B1/GRP94) as a key mediator of this toxicity. A natural product screen suggested ligustilide as a potential protective agent. Computational docking revealed that both ligustilide and the representative PFAS compound OBS target the Asn107 site on GRP94. Subsequent site-directed mutagenesis and knockdown-rescue experiments confirmed that OBS binding at Asn107 induces N-glycosylation of GRP94. Ligustilide competitively occupies this site, thereby blocking OBS-induced glycosylation, restoring GRP94's chaperone function, and alleviating endoplasmic reticulum stress and apoptosis. In PFAS-exposed diabetic rats, ligustilide treatment effectively rescued impaired wound healing, as evidenced by accelerated wound closure, improved tissue perfusion and vascular maturation, and enhanced collagen deposition. Our findings elucidate a novel mechanism through which PFAS disrupt tissue repair via precise glycosylation of GRP94 and highlight ligustilide as a promising therapeutic candidate against PFAS-aggravated diabetic complications.