This study reveals the central role of FABP5 in psoriatic skin inflammation, suggesting it functions as a downstream effector molecule independent of the IL-17A pathway. These findings provide a theoretical basis for developing novel therapeutic strategies targeting the intersection of lipid metabolism and ferroptosis, particularly for psoriasis patients who respond poorly to current biologics.
Literature Overview
The article titled 'Fatty acid-binding protein 5 aggravates psoriasis and psoriasis-like disease through ferroptosis,' published in the journal Cell Death and Differentiation, systematically investigates the pathogenic mechanisms of fatty acid-binding protein 5 (FABP5) in psoriasis and its associated psoriatic arthritis (PsA). Using an epidermis-specific c-Jun/JunB double knockout (DKO*) mouse model, combined with transcriptomic, proteomic, and clinical sample validation, the authors demonstrate that functional imbalance between FABP5 and glutathione peroxidase 4 (GPX4) drives ferroptosis to exacerbate skin inflammation—a process reversible by FABP inhibitors or ferroptosis inhibitors. The study further shows that existing biologics can restore the FABP5/GPX4 expression balance, indicating that this axis is not only a potential therapeutic target but also a candidate biomarker for treatment response.Background Knowledge
Psoriasis is a chronic inflammatory skin disease driven primarily by aberrant activation of T cells and keratinocytes (KCs), often accompanied by systemic complications such as PsA and cardiovascular diseases, significantly impairing patients’ quality of life. Although biologics targeting cytokines like IL17A and TNFα have dramatically improved treatment outcomes, a substantial proportion of patients still exhibit suboptimal responses or develop resistance, suggesting the existence of pathogenic mechanisms independent of the Th17 pathway. Recently, oxidative stress and lipid peroxidation have gained increasing attention in psoriasis pathogenesis. Ferroptosis, an iron-dependent form of regulated cell death characterized by reduced GPX4 activity and accumulation of lipid ROS, has been observed in patient skin lesions. However, the key upstream regulators driving ferroptosis remain unclear. While FABP5, a fatty acid transport protein, has been reported to be upregulated in inflammation, its role in psoriasis progression—particularly its connection to ferroptosis—has not been systematically elucidated. This study addresses this mechanistic gap by proposing FABP5 as a critical node linking lipid metabolic dysregulation and ferroptosis, offering a new perspective on psoriasis pathogenesis.
Research Methods and Experiments
The study employed an epidermis-specific inducible c-Jun and JunB double knockout (DKO*) mouse model as a preclinical model of psoriasis, which spontaneously develops skin thickening, immune cell infiltration, and arthritis-like lesions, closely mimicking human PsA. RNA-seq and proteomic analyses of both DKO* mice and psoriatic patient skin lesions revealed upregulation of FABP5 and downregulation of GPX4, with significant enrichment in lipid metabolism and ferroptosis pathways. Pharmacological intervention with the FABP inhibitor BMS309403 significantly improved skin phenotypes, restored GPX4 protein levels, reduced lipid peroxidation product 4-HNE, and decreased neutrophil infiltration, without affecting systemic IL-17a levels—indicating that FABP5 acts downstream of IL-17a. Additionally, treatment with the ferroptosis-specific inhibitor Liproxstatin-1 alleviated skin lesions but did not affect joint pathology, further supporting a skin-specific role of ferroptosis in inflammation.Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the FABP5-GPX4-ferroptosis axis as a core mechanism in psoriatic skin inflammation, expanding our understanding of disease pathogenesis. From a drug development perspective, FABP5 emerges as a novel therapeutic target following IL17A and TNFα, especially for patients with inadequate responses to current biologics, and its inhibitors may avoid systemic immunosuppression. In clinical monitoring, FABP5 levels in skin or serum could serve as biomarkers for disease activity or treatment response, enabling precision medicine. Furthermore, this mechanism provides new directions for building disease models that better reflect human pathology—such as developing keratinocyte-specific FABP5 overexpression or GPX4 knockout mice—to simulate chronic inflammatory microenvironments.
Conclusion
This study mechanistically uncovers a novel pathway in which FABP5 drives psoriatic skin inflammation by suppressing GPX4 function and promoting ferroptosis. This finding not only reveals a critical interplay between lipid metabolism and regulated cell death in psoriasis but also complements current IL17A-centered treatment paradigms. Notably, FABP5 upregulation is reversible by anti-IL17A therapy, positioning it downstream in the inflammatory cascade and as one of the effector nodes through which biologics exert their effects. Therefore, targeting FABP5 or ferroptosis may offer new options to enhance or replace existing therapies, especially for patients with refractory skin lesions. Future studies should further explore the role of FABP5 in different cell types (e.g., dendritic cells, neutrophils) and evaluate its prognostic value in human psoriasis cohorts. From bench to bedside, this work lays a solid foundation for constructing a three-dimensional network of 'inflammation-metabolism-cell death,' potentially advancing psoriasis care toward more precise and stratified treatment models.
