The protective impact of myricetin against PM2.5-induced cellular apoptosis by inhibiting endoplasmic reticulum stress

Particulate matter 2.5 (PM_2.5) exposure is responsible for skin inflammation, aging, and disruption of skin homeostasis. The objective of this investigation was to assess the potential of myricetin in protecting against skin damage caused by PM_2.5. Human keratinocytes (HaCaT) were pretreated with myricetin and subsequently exposed to PM_2.5. Cell viability, reactive oxygen species (ROS) generation, oxidized cellular components, mitochondrial damage, cellular apoptosis, and endoplasmic reticulum (ER) stress were assessed. A mitogen-activated protein kinase (MAPK) signaling network was constructed, and the action site of myricetin was explored through docking analysis. PM_2.5 induced oxidative stress, resulting in DNA damage, lipid peroxidation, protein carbonylation, and cellular apoptosis. Myricetin counteracted these effects by reducing the PM_2.5-induced ROS levels. Additionally, myricetin mitigated the PM_2.5-induced cytochrome c release into the cytoplasm and caspase activation, thereby ameliorating cellular apoptosis. Myricetin reduced PM_2.5-induced cytosolic Ca²⁺ level and ER-related signaling molecules. Furthermore, myricetin inhibited cellular cytotoxicity by downregulating the MAPK signaling pathway. Docking and network analyses identified 12 major MAPK proteins targeted by myricetin, and these proteins primarily affected the classical MAPK pathway. These findings suggest that myricetin mitigates skin impairments caused by PM_2.5 exposure by reducing ROS, mitochondrial damage, ER stress, and apoptosis via downregulating the MAPK signaling pathway.