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Multi-Omics Reveals That Hydroxypinacolone Retinoate Alleviates UV-Induced Skin Aging via the p38/MMP9/Collagen Axis
Haotian Wu1, Shuiying Zheng1, Huihong Wen1
1Departments of Dermatology, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, Guangdong Province, People's Republic of China.
Introduction:
UV radiation induces skin photoaging via the p38/MMP9/collagen axis. Hydroxypinacolone Retinoate (HPR) is a retinoic acid precursor with anti‑aging potential, but its concentration-dependent mechanisms remain unclear. This study investigates how HPR protects against UV-induced photoaging through this axis using in vivo experiments combined with transcriptomics and metabolomics.
Methods:
A chronic photoaging model was established in KM mice by UVB irradiation (100 mJ/cm2, every other day for 4 weeks) on the dorsal skin. Topical HPR at concentrations of 0.025%, 0.5%, or 1% was applied immediately after each UV exposure. Histological evaluations included H&E staining for epidermal thickness, Toluidine blue for mast cell infiltration, and Masson's trichrome for collagen deposition. Immunohistochemistry was used to detect collagen I, MMP9, and phosphorylated p38 (p-p38). ELISA measured PIP, TGF-β1, MMP9, TIMP1, elastin, GPX4, ACSL4, and IL-10. Multi-omics analyses (RNA-seq transcriptomics and LC-MS metabolomics) were performed with GO/KEGG enrichment.
Results:
HPR dose‑dependently improved macroscopic and histological photoaging signs, reducing epidermal hyperplasia and mast cell infiltration while restoring collagen deposition. It upregulated collagen synthesis markers (PIP, TGF‑β1, collagen I) and IL‑10, downregulated MMP9 and p‑p38, corrected the MMP9/TIMP1 balance, preserved elastin, restored GPX4 activity, and suppressed ACSL4. Multi‑omics revealed concentration‑dependent effects: low‑dose HPR affected metabolic pathways, medium‑dose enriched autophagy, and high‑dose triggered immune‑inflammatory rebalancing.
Discussion:
HPR alleviates photoaging through coordinated mechanisms: promoting collagen synthesis, inhibiting MMP9‑mediated degradation, preserving elastin, reducing oxidative stress and ferroptosis, and shifting inflammation toward repair via IL‑10, while suppressing the p38/MMP9 axis. The dose‑dependent hormetic response-metabolic adaptation at low dose, autophagy at medium dose, immune modulation at high dose-supports HPR as a multi‑target agent for skin rejuvenation.