Beyond IL-23/IL-17: Novel Pathogenic Mechanisms

The IL-23/IL-17 axis remains the central pathogenic pathway in psoriasis (Section 6.3), but recent research has uncovered several additional mechanisms that contribute to disease initiation, amplification, and chronicity. These discoveries are expanding the therapeutic target landscape and helping explain why psoriasis behaves the way it does.

7.1 Ferroptosis: Iron-Dependent Keratinocyte Death

Ferroptosis is a recently characterised form of regulated cell death driven by iron-dependent lipid peroxidation, the oxidative destruction of lipids (fats) in cell membranes. Unlike apoptosis (programmed cell death that’s orderly and immunologically silent), ferroptosis is inherently inflammatory: dying cells release damage-associated molecular patterns (DAMPs) that activate the innate immune system.

In psoriasis, K14-expressing keratinocytes, the predominant cell type in the epidermis, undergo ferroptotic death. A landmark 2024 study demonstrated that mice lacking glutathione peroxidase 4 (Gpx4) in epidermal keratinocytes developed a psoriasiform phenotype with characteristic Th1/Th17 immune responses in both skin and extracutaneous tissues (Shou et al., 2024). Here’s the key finding: the ferroptosis inhibitor liproxstatin-1 showed efficacy comparable to biologics targeting IL-12, IL-23, and TNF-a in this model. That suggests ferroptosis may be an upstream initiating event rather than a downstream consequence (Shou et al., 2024).

Human psoriatic skin shows elevated markers of ferroptosis, including increased iron deposition, lipid peroxidation products (such as 4-hydroxynonenal), and reduced expression of ferroptosis-suppressing genes. This connects to the hepcidin/iron dysregulation findings discussed in Section 27.9, pointing to a broader role for iron metabolism in psoriasis pathogenesis (Abboud et al., 2024; cited in Section 27.9).

Research stage: Emerging. Evidence strength: Moderate. Supported by human tissue analyses and murine knockout models, but no clinical trials of ferroptosis inhibitors in psoriasis patients yet.

7.2 Trained Immunity and Epigenetic Stem Cell Memory

A fundamental question in psoriasis: why does the disease relapse at the same anatomical sites? The answer increasingly points to trained immunity, a concept describing how innate immune cells and tissue stem cells retain a long-term “memory” of prior inflammation through epigenetic modifications, even without adaptive immune memory.

In psoriasis, two forms of trained immunity have been identified:

Epidermal stem cell memory. Epidermal stem cells in previously affected skin maintain open chromatin at inflammation-responsive gene loci long after clinical resolution. This persistent chromatin accessibility allows rapid gene re-activation upon secondary insult, effectively a “hair trigger” for relapse (Cell Research, 2025). The STEPIn trial (Section 19.2) provided clinical evidence that early biologic treatment can reverse these epigenetic changes, while delayed treatment was less effective at doing so. The implication: the epigenetic “scarring” may become progressively harder to erase, though long-term follow-up data are still being collected.

Monocyte training. LL-37/self-DNA complexes, the same danger signals that initiate the psoriatic cascade (Section 6.2), also induce long-term metabolic and epigenetic reprogramming in circulating monocytes. Trained monocytes exhibit heightened glycolytic rates and produce elevated levels of pro-inflammatory cytokines upon restimulation, even weeks or months after the initial exposure (Tankov & Rorvig, 2025). This systemic “priming” may explain why psoriasis is a systemic disease with extracutaneous manifestations.

These findings have real therapeutic implications. If epigenetic memory drives chronicity, then therapies that erase or reprogram this memory (Section 28.6) could achieve true disease modification rather than mere suppression.

Research stage: Emerging. Evidence strength: Moderate. Mechanistic studies in human tissue and monocytes, with clinical correlation from the STEPIn trial. No direct therapeutic targeting of trained immunity in psoriasis trials yet.

7.3 The IL-36 Axis: A Distinct Autoinflammatory Pathway

The IL-23/IL-17 axis dominates plaque psoriasis pathogenesis, but generalised pustular psoriasis (GPP) and some forms of palmoplantar pustulosis run on a different engine entirely. They’re driven by a distinct autoinflammatory pathway centred on the IL-36 family of cytokines (IL-36a, IL-36b, IL-36g). Loss-of-function mutations in the IL-36 receptor antagonist gene (IL36RN) cause unrestrained IL-36 signalling, leading to massive neutrophil recruitment and pustule formation.

Neutrophil extracellular traps (NETs), web-like structures of DNA that neutrophils release to trap pathogens, play a critical amplifying role. NETs enhance keratinocyte-derived IL-36 production and stimulate CCL20 secretion, which recruits more neutrophils. The result is a self-propagating inflammatory loop distinct from the Th17/IL-17 feed-forward cycle (Watanabe et al., 2025).

Clinical validation of this pathway came with spesolimab, an anti-IL-36 receptor antibody that received regulatory approval for GPP flares after demonstrating rapid pustule clearance in the Effisayil 1 and Effisayil 2 trials. Spesolimab mitigates residual inflammation even after acute flare resolution and reduces flare recurrence (Bachelez et al., 2024). Imsidolimab, another anti-IL-36 receptor antibody, is in Phase 3 development.

Recognising IL-36 as a separate axis has shifted how we classify psoriasis: GPP is now increasingly understood as an autoinflammatory disease (driven by innate immunity) rather than an autoimmune disease (driven by adaptive immunity), with potential overlap in some patients.

Research stage: Established for GPP. Evidence strength: High. Phase 3 RCT data for spesolimab; genetic basis well-characterised through IL36RN mutations.

7.4 Autophagy Dysfunction

Autophagy is the cell’s self-cleaning process, a mechanism by which cells digest and recycle their own damaged components. In healthy skin, autophagy acts as a brake on inflammation by clearing damaged organelles and misfolded proteins that would otherwise activate innate immune sensors.

In psoriasis, this protective mechanism is impaired. Mutations in AP1S3, a gene encoding a subunit of the AP-1 adaptor protein complex involved in intracellular vesicle trafficking, disrupt autophagy and lead to abnormal accumulation of p62 (an autophagy cargo receptor). Accumulated p62 activates the NF-kB signalling cascade (Section 6.5), resulting in accelerated IL-1 signalling and overexpression of IL-36a. That directly connects autophagy dysfunction to the IL-36 axis described above (Mahil et al., 2024).

Now, IL-17A itself also impairs autophagy in keratinocytes, creating a vicious cycle: IL-17A drives inflammation while simultaneously disabling the cell’s ability to resolve it (Zhang et al., 2025). This dual effect may partly explain why IL-17 blockade works so well in psoriasis. It breaks the inflammatory cycle at multiple points simultaneously.

Research stage: Emerging. Evidence strength: Low-Moderate. Primarily cell and molecular studies with genetic validation through AP1S3 mutations. No autophagy-targeting therapies in psoriasis clinical trials.

7.5 Extracellular Vesicles and Exosomes

Extracellular vesicles (EVs), including exosomes (30-150 nm diameter) and microvesicles (100-1000 nm), are tiny membrane-enclosed parcels released by virtually all cell types. They carry proteins, lipids, and nucleic acids (including microRNAs) and function as long-range molecular messengers.

In psoriasis, serum-derived exosomes modify keratinocyte behaviour by upregulating pro-inflammatory cytokine production and inducing oxidative stress (Jiang et al., 2024). The cargo of psoriatic EVs differs from that of healthy individuals, with enrichment in inflammatory microRNAs and altered lipid profiles (Lu et al., 2024).

EVs are also being explored in two translational directions:

• As biomarkers: EV cargo composition may reflect disease activity and treatment response. Patients treated with biologics show normalisation of EV lipid profiles, suggesting EVs could serve as non-invasive monitoring tools.
• As drug delivery vehicles: Engineered exosomes loaded with therapeutic agents (such as EGCG, a green tea polyphenol with anti-inflammatory properties) can deliver drugs specifically to inflamed skin, potentially improving topical treatment efficacy while reducing systemic exposure.

Research stage: Experimental. Evidence strength: Low. In vitro studies and observational human data. No clinical trials using EV-based diagnostics or therapeutics in psoriasis.

7.6 Oxidative Stress and Lipid Peroxidation

Oxidative stress, an imbalance between reactive oxygen species (ROS) production and the body’s antioxidant defences, is consistently elevated in psoriatic skin and blood. This isn’t merely a bystander effect of inflammation. It’s an active contributor to disease pathology.

Psoriatic patients show altered plasma lipid profiles, with increased lipid peroxidation products and decreased levels of protective antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase). Metabolomics studies using liquid chromatography-mass spectrometry (LC-MS) have identified dysregulation of amino acids, carnitines, fatty acids, and lipids that correlate with disease severity and improve with anti-TNF treatment (Sorokin et al., 2024).

Oxidative stress connects to ferroptosis (Section 7.1) through a shared mechanism: lipid peroxidation. When antioxidant defences fail and iron is available to catalyse free radical reactions, membrane lipids are oxidised, triggering ferroptotic cell death. This mechanistic link suggests that antioxidant supplementation or iron chelation could theoretically modulate psoriasis, though clinical evidence for these approaches remains limited (Section 19).

Research stage: Emerging. Evidence strength: Moderate. Multiple metabolomics studies in human cohorts; mechanistic link to ferroptosis established in preclinical models. Antioxidant interventions have not demonstrated consistent clinical benefit.