Long-chain chlorinated paraffins trigger intestinal toxicity through mitochondrial dysfunction-driven cellular senescence and inflammation

Long-chain chlorinated paraffins (LCCPs), often used as alternatives to short- and medium-chain chlorinated paraffins, have been detected as residues in air, water, and soil. However, the toxic effects of LCCPs on intestinal cells and tissues, as well as the underlying molecular mechanisms, remain largely unexamined. This study investigates LCCPs-induced intestinal cell senescence and elucidates the associated molecular mechanisms. Cell proliferation and senescence were measured using relevant assay kits, while the expression levels of senescence- and inflammation-related proteins in intestinal cells and tissues were assessed by Western blot analysis. Additionally, the protein levels of retinoic acid-inducible gene I (RIG-I), mitochondrial antiviral signaling protein (MAVS), and key mitophagy markers were evaluated. The interaction between LCCPs and PTEN-induced putative kinase 1 (PINK1) was confirmed using Drug Affinity Responsive Target Stability (DARTS), the Cellular Thermal Shift Assay (CETSA), and molecular docking techniques. Our findings indicate that LCCPs induce intestinal inflammation, cellular senescence, and mitochondrial dysfunction via activation of the RIG-I-MAVS pathway and direct binding to PINK1, which inhibits mitophagy. Furthermore, LCCPs also provoke inflammatory and senescence-related damage in intestinal tissues. Overall, LCCPs' binding to PINK1, suppression of mitophagy, and activation of the RIG-I-MAVS signaling pathway contribute to intestinal senescence and inflammatory injury.