Solanesol Alleviates Perfluoroheptanoic Acid‐Induced Premature Senescence in Human Skin Fibroblasts via RNA Methylation

Perfluoroheptanoic acid (PFHpA), an emerging persistent organic pollutant, is increasingly used as a substitute for conventional perfluorinated compounds. Exposure to PFHpA increases the risk of skin damage and contributes to skin senescence. However, the epigenetic mechanisms underlying its dermal toxicity remain largely unknown. Natural plant compound solanesol exhibits biological activities including antioxidant and anti‐inflammatory effects, demonstrating potential application value in delaying skin cellular senescence. This study aims to investigate the regulatory roles of m6A and m5C RNA methylation in perfluoroheptanoic acid (PFHpA)‐induced premature senescence of human skin fibroblasts (HSFs), as well as the intervening effects of low‐dose solanesol. Our data demonstrated that solanesol reduced SA‐β‐gal staining, ROS levels, and the expression of the senescence‐associated secretory phenotype (SASP) factors in HSFs, likely through enhancing cell viability. Moreover, solanesol ameliorated PFHpA‐induced dysregulation of RNA methyltransferases including VIRMA, METTL3, METTL14, and WTAP. Key genes such as AKT1, NSUN2, and ALYREF were further identified to be involved in solanesol‐mediated attenuation of premature senescence. Collectively, these findings not only elucidate the role of RNA methylation in PFHpA‐induced skin fibroblast senescence but also highlight the potential of low‐dose solanesol as a plant‐derived epigenetic modulator. This study provides mechanistic insights into the dermal toxicity of emerging PFAS substitutes and suggests a preventive strategy against environment‐associated skin cellular senescence, which holds implications for future health risk assessment of persistent organic pollutants.