COTL1 (coactosin-like F-actin binding protein 1) is an actin-binding protein that regulates cytoskeletal dynamics and serves as a functional chaperone for 5-lipoxygenase (ALOX5). Mechanistically, COTL1 binds F-actin in a calcium-independent manner 1 and protects actin filaments from cofilin-mediated depolymerization, thereby promoting lamellipodial protrusion during T cell immune responses 1. As an ALOX5 chaperone, COTL1 influences leukotriene synthesis and ferroptosis regulation 2. COTL1 has emerging disease relevance across multiple pathologies. In intracerebral hemorrhage, COTL1 expression correlates with oxidative stress severity in microglia (r=0.69, p<0.05) and may enter the brain via monocytes 3. Elevated COTL1 protein expression associates with poor prognosis in breast cancer and increased immune cell infiltration 4. In oesophageal squamous cell carcinoma, COTL1 overexpression upregulates PD-L1 and promotes proliferation 5. COTL1 gene polymorphisms (c.-1124G>T and c.484G>A) associate with genetic susceptibility to rheumatoid arthritis and systemic lupus erythematosus 6, and COTL1-ALOX5 interaction regulates ferroptosis in RA pathogenesis 2. Additionally, maternal COTL1 genetics influence human milk microbiota composition, affecting childhood asthma and atopy risk 7. These findings suggest COTL1 represents a potential therapeutic target across inflammatory, autoimmune, and malignant conditions.