Hydroxypinacolone 9-cis retinoate mitigates UV-induced photoaging by modulating extracellular matrix, fibroblasts, inflammation, and melanogenesis.

Photoaging, driven by chronic UVR, disrupts skin structure and function. Traditional retinoids enhance extracellular matrix regeneration but cause irritation. Hydroxypinacolone 9-cis retinoate (9-cis HPR), a derivative of 9-cis retinoic acid, selectively activates retinoic acid receptor α and retinoid X receptor α, improving efficacy and tolerability. In a UVR-induced SKH-1 mouse photoaging model, 9-cis HPR reduced erythema, desquamation, and loss of elasticity while promoting collagen and elastin production. Single-cell RNA sequencing and spatial transcriptomics revealed restoration of fibroblast, basal cell, and melanocyte proportions; suppression of myofibroblast differentiation; and upregulation of extracellular matrix-related genes (eg, Col1a2, Col3a1, Elastin). In addition, 9-cis HPR inhibited melanogenesis by downregulating melanogenesis-related genes (Tyr, Dct, Tyrp1), melanosome biogenesis genes (Mlana, Pmel), and the melanocyte proliferation gene Kit, likely through ROS suppression. Cell-cell interaction analysis showed that 9-cis HPR promoted fibroblast-driven repair through neuropeptide Y-NPY1R, PTN-SDC2, and POSTN-ITGA/BV signaling, while inhibiting KITL-KIT-mediated melanocyte proliferation. In a single-blind, split-face clinical trial involving 31 Chinese women, 0.03% 9-cis HPR applied daily for 4 weeks demonstrated comparable or superior improvements in wrinkles, elasticity, hydration, dermal density, and radiance versus 0.3% retinol, without observed irritation. These findings support 9-cis HPR as a safe and effective retinoid that mitigates photoaging through extracellular matrix restoration, inflammation modulation, and pigmentation control.