Emerging evidence suggests that psoriatic skin may exhibit increased cholesterol synthesis and downstream signaling, which may contribute to psoriasis pathobiology by promoting proinflammatory pathways.
In a perspective, lead author Andrzej T. Slominski, of the Department of Dermatology at the University of Alabama at Birmingham, and colleagues outlined a mechanistic hypothesis for why ultraviolet B (UVB) phototherapy may be an effective treatment option in patients with psoriasis that may extend beyond its established immunosuppressive effects. Central to this framework is a relatively underappreciated pathway: cholesterol and its downstream oxysterols can act as ligands for retinoic acid orphan receptor (ROR)-gamma, a nuclear receptor capable of regulating interleukin (IL)-17 signaling—the same proinflammatory axis targeted by modern biologic therapies.
The perspective authors proposed that UVB radiation may disrupt this pathway at multiple points. UVB exposure can photolyze the cholesterol precursors 7-dehydrocholesterol and 7-dehydrodesmosterol, potentially reducing substrate availability for cholesterol synthesis. At the same time, these precursors are converted into vitamin D3, lumisterol, and tachysterol, which can undergo enzymatic hydroxylation to produce metabolites that act as inverse agonists of ROR-gamma—an effect established for vitamin D and lumisterol derivatives and likely for tachysterol derivatives. The therapeutic rationale for vitamin D–derived compounds in psoriasis is supported by the proposed mechanisms, although clinical validation remains limited, with more sparse evidence for lumisterol and tachysterol derivatives.
Taken together, the authors hypothesize that UVB phototherapy may exert anti-inflammatory effects through at least three complementary mechanisms: attenuation of cholesterol synthesis; generation of endogenous steroidal and secosteroidal metabolites that inhibit ROR-gamma and downstream IL-17 signaling; and activation of the vitamin D receptor, which can suppress nuclear factor–kappa–light-chain-enhancer of activated B cells–mediated inflammatory responses. This framing suggests that UVB phototherapy may act through coordinated metabolic and signaling pathways rather than through immunosuppression alone.
Whether these mechanisms can be translated into pharmacologic therapies remains uncertain. The perspective authors highlighted noncalcemic and nontoxic CYP11A1-derived vitamin D metabolites—such as 20(OH)D3 and 20,23(OH)₂D3—as potential candidates, though much of the proposed cascade remains based on mechanistic inference. In particular, the role of lumisterol and tachysterol derivatives in ROR-gamma signaling will require further validation, and the contribution of the Bloch pathway to cholesterol synthesis in human skin is not yet fully defined.
Still, the broader implication is notable: if cholesterol metabolism is an important contributor to psoriatic inflammation, it may prompt a reassessment of both disease biology and the mechanisms underlying established therapies such as UVB phototherapy.
“[The findings] open new perspectives for educated photo and/or chemotherapeutic approaches for the treatment of this common hyperproliferative inflammatory disorder,” the perspective authors concluded.
The authors’ full disclosures are reported in the original perspective.
