Chronic ER stress couples cellular senescence with pigment retention

Abstract

Solar lentigines are characterized by persistent basal hyperpigmentation. We hypothesized that chronic IRE1α-mediated ER stress simultaneously increases melanocyte melanogenesis and impairs keratinocyte melanophagic clearance, generating a pigment-retention state. We analyzed paired lesional/non-lesional skin and used melanocyte (MNT-1) and keratinocyte (HaCaT) models with doxycycline-inducible or constitutive IRE1α to quantify melanogenesis, melanosome transfer/retention, lysosomal acidity (LysoTracker), autophagic flux (mRFP–GFP–LC3), and cathepsin maturation; verapamil and the IRE1α RNase inhibitor STF083010 served as interventions. Lesional epidermis exhibited dense stage-IV melanosomes with increased IRE1α and p16. Sustained IRE1α reduced proliferation and increased p16/p21. In melanocytes, IRE1α increased tyrosinase activity and melanin with more/larger melanosomes. In keratinocytes, IRE1α raised intracellular melanosomes by slowing degradation, with diminished LysoTracker signal, reduced cathepsin-B maturation, and fewer autolysosomes. Verapamil or STF083010 lessened melanosome accumulation and partially restored degradation. Thus, chronic IRE1α enforces a dual-hit program characterized by enhanced melanogenesis and impaired melanophagy, implicating the IRE1α and lysosome axis as a potential therapeutic target.