Document Type

Article

Publication Title

Taming Psoriatic Inflammation: Targeting The iNOS–Oxidative Stress–Necroptosis Axis For Precision Therapy

Abstract

Necroptosis is increasingly recognized as a central driver of psoriatic inflammation, promoting keratinocyte death and sustaining immune activation. Recent evidence shows that inducible nitric oxide synthase (iNOS) deficiency and exogenous nitric oxide (NO) supplementation ameliorate psoriasis-like dermatitis in mice by reducing oxidative stress and constraining necroptotic signaling. These findings identify iNOS-derived NO as both a mediator of reduction–oxidation (redox) imbalance and a key regulator of necroptosis, thereby advancing mechanistic insight into psoriatic pathogenesis. Importantly, they highlight the iNOS–oxidative stress–necroptosis axis as a translationally actionable therapeutic target. Modulating necroptotic cell death through NO-based interventions may restore epidermal homeostasis and improve clinical outcomes, offering new opportunities to reshape therapeutic strategies in psoriasis and related inflammatory skin disorders.

First Page

Necroptosis is increasingly recognized as a central driver of psoriatic inflammation, promoting keratinocyte death and sustaining immune activation. Recent evidence shows that inducible nitric oxide synthase (iNOS) deficiency and exogenous nitric oxide (NO) supplementation ameliorate psoriasis-like dermatitis in mice by reducing oxidative stress and constraining necroptotic signaling. These findings identify iNOS-derived NO as both a mediator of reduction—oxidation (redox) imbalance and a key regulator of necroptosis, thereby advancing mechanistic insight into psoriatic pathogenesis. Importantly, they highlight the iNOS—oxidative stress—necroptosis axis as a translationally actionable therapeutic target. Modulating necroptotic cell death through NO-based interventions may restore epidermal homeostasis and improve clinical outcomes, offering new opportunities to reshape therapeutic strategies in psoriasis and related inflammatory skin disorders. In a recent study, Sun et al (2025) reveal that iNOS-derived NO triggers keratinocyte necroptosis and epidermal inflammation in psoriasis. Necroptosis, a form of programmed necrotic cell death that promotes keratinocyte death and sustains immune activation, is increasingly recognized as a key driver of inflammatory skin diseases. This work identifies iNOS-derived NO-mediated redox imbalance as a central regulator of epidermal homeostasis and a potential therapeutic target in psoriatic disease. Psoriasis exemplifies a T helper (Th)1/Th17-driven inflammatory dermatosis characterized by hyperproliferative, aberrantly differentiated keratinocytes that perpetuate immune

Last Page

CONCLUDING REMARKS By uncovering the mechanistic axis connecting iNOS derived NO, necroptosis, and epidermal inflammation, Sun et al (2025) redefine the pathogenic landscape of psoriasis. Targeting the iNOS—oxidative stress—necroptosis pathway offers a rational framework for disease-modifying therapies that move beyond symptomatic control toward restoration of epidermal homeostasis and long-term remission. In conclusion, modulating the iNOS—oxidative stress—necroptosis circuitry represents a promising direction toward disease-modifying therapy, moving psoriasis management beyond symptomatic control toward restoration of epidermal homeostasis and durable remission. It is anticipated that dual targeting of iNOS—PI3K/Akt/mTOR axis represents a promising precision approach to disrupt self amplifying inflammatory loops, restore redox homeostasis, and promote epidermal repair in psoriasis

DOI

doi:10.1016/j.jid.2025.11.026

Publication Date

1-29-2026

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