ACSL1 orchestrates ferroptosis and degranulation in low-density neutrophils: a novel pathogenic mechanism and therapeutic target in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which neutrophils, especially the pro-inflammatory low-density neutrophil (LDN) subset, play a central pathogenic role. Yet, the molecular mechanisms that link neutrophil ferroptosis, degranulation, and interferon amplification remain incompletely understood. Through integrative bioinformatics and validation in clinical samples, we identified acyl-CoA synthetase long-chain family member 1 (ACSL1) as a pivotal regulator in SLE. ACSL1 expression was consistently elevated in patient-derived neutrophils, with the highest levels observed in LDNs. Elevated ACSL1 strongly correlated with signatures of ferroptosis, mitochondrial dysfunction, neutrophil degranulation, and type I interferon responses. Single-cell RNA sequencing further revealed ACSL1 enrichment along the trajectory of neutrophil differentiation toward a transcriptional state consistent with pathogenic LDNs, suggesting a potential role in shaping their inflammatory phenotype that warrants further experimental validation. Importantly, molecular docking identified several small-molecule compounds, including the FDA-approved drug fenofibrate, with strong predicted binding to ACSL1. Together, these findings establish ACSL1 as a novel dual regulator orchestrating ferroptosis and degranulation in LDNs, thereby bridging mitochondrial dysfunction with aberrant immune activation in SLE. Targeting ACSL1 may represent a feasible approach to restrain neutrophil-driven inflammation with reduced risk of broad immunosuppression, highlighting its potential as a precision therapeutic target in systemic lupus erythematosus and related autoimmune conditions.