Immune dysregulation in fibromyalgia: Targeting the NLRP3 inflammasome-ferroptosis axis as a novel therapeutic strategy for chronic pain

Clin Immunol. 2026 Apr 8:110704. doi: 10.1016/j.clim.2026.110704. Online ahead of print.

ABSTRACT

Fibromyalgia (FM) is a chronic pain syndrome with neuroinflammation and oxidative stress as key features. Emerging evidence implicates a pathogenic interplay between the NLRP3 inflammasome and ferroptosis, an iron-dependent cell death driven by lipid peroxidation. This review describes a self-sustaining inflammato-ferroptotic axis, where dysregulation of glutathione peroxidase 4 (GPX4) (protective) and arachidonate 15-lipoxygenase (ALOX15) (pro-ferroptotic) facilitates lipid peroxidation, releasing DAMPs that activate NLRP3 and amplify central sensitization. Conversely, NLRP3-driven inflammation exacerbates oxidative stress, further inducing ferroptosis. We highlight this axis as a novel therapeutic paradigm, proposing strategies to inhibit NLRP3, enhance GPX4, or block ALOX15. However, the lack of direct clinical evidence for ferroptosis in FM patients limits this review. Future perspectives require translational studies validating ferroptosis biomarkers in patient cohorts and preclinical testing of combinatorial therapies targeting both pathways to establish efficacy and safety before clinical application.

PMID:41962813 | DOI:10.1016/j.clim.2026.110704