FP02 Phototoxic drug reactions alter the cutaneous lipidome and initiate ferroptosis in skin cells

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ID: 318470
2026
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Abstract
Abstract Introduction and aims Drug-induced photosensitivity (DIP) is a reaction to sunlight, principally to ultraviolet (UV)A, affecting individuals using common medications. The molecular mechanism underpinning DIP is partly attributed to phototoxic reactions causing oxidative damage to biomolecules, including phospholipids. Although oxidized phospholipids are involved in inflammation, their role in DIP is unexplored. We examined the impact of phototoxic drugs on the lipidome of epidermal keratinocytes and ferroptosis, a lipid oxidation-linked cell death pathway. Methods HaCaT keratinocytes were treated with known phototoxic drugs: hydrochlorothiazide (HCTZ) (0.24–750 μmol L–1), naproxen (NAP) (6–750 μmol L–1), quinine (QUIN) (0.24–750 μmol L–1) and 8-methoxypsoralen (8-MOP) 0.07–220 μmol L–1), and exposed to UVA (5 J cm−2). Cells were treated with drugs before UVA exposure or were exposed to drugs and UVA concurrently. Cell viability was assessed; cellular lipids were extracted from vehicle-control, UVA-only, drug-only, and drug + UVA-treated cells, 0 h and 24 h post-treatment. Untargeted lipidomics was performed using ultrahigh performance supercritical fluid chromatography coupled to quadrupole time-of-flight mass analyser with electrospray ionization. The involvement of ferroptosis was explored using ferrostatin-1 (50 µmol L–1). Results Immediate generation of oxidized phosphatidylcholine species was observed in NAP, QUIN and 8-MOP photosensitized cells, returning to baseline within 24 h. UVA exposure of NAP-pretreated cells did not alter the lipidome, but concurrent NAP + UVA ­exposure reduced all tested phospholipid classes (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylglycerol). UVA exposure of HCTZ or 8-MOP-pretreated cells increased phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine) and neutral lipids (diacylglycerol, triacylglycerol, cholesteryl ester), while QUIN + UVA treatment increased ­sphingomyelin, lysophosphatidylcholine and cholesteryl esters. Ferrostatin-1 prevented cell death caused by NAP and QUIN phototoxicity. Conclusions These findings suggest that phototoxic drug reactions alter the cutaneous lipidome, indicating a role for cellular lipids in DIP. Lipid changes may be part of a protective mechanism for subthreshold oxidative stress, while accumulation of oxidized phospholipids might initiate ferroptotic cell death. Better understanding of this response can help identify future treatment targets.
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Authors Aliye Bashak, Alexandra Kendall, Mark Farrar, Xiaoqi Ma, Michael Morris, Lesley E. Rhodes, Anna Nicolaou
Journal the british journal of dermatology
Year 2026
DOI
10.1093/bjd/ljag151.025
URL
https://doi.org/10.1093/bjd/ljag151.025
Keywords Keywords not found

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