Unveiling natural anti-inflammatory compounds for sinusitis treatments by modulating FOXP3, C5aR1, and LIF

Chronic rhinosinusitis (CRS) is a condition with a significant healthcare and economic burden, with a prevalence of 12% in the West. The existing therapies mainly attenuate downstream inflammatory mediators but do not address the underlying immune-regulatory abnormalities that drive disease recurrence and lifelong treatment. Evidence has shown that a regulatory axis involving forkhead box P3 (FOXP3) + regulatory T cells (Tregs), the complement component 5a receptor 1 (C5aR1), and leukemia inhibitory factor (LIF) is crucial for regulating immune tolerance in sinonasal tissues. This review discusses the mechanistic basis for modulating FOXP3, C5aR1, and LIF with natural anti-inflammatory products for the treatment of CRS. A comprehensive literature review across PubMed, Scopus, and Web of Science (2000-2026) was conducted to identify research articles on the molecular mechanisms, preclinical evidence, and clinical application of natural compounds in inflammatory disorders and the sinonasal inflammatory pathway. Various studies show that FOXP3+ Tregs are highly depleted in CRS with nasal polyps. Besides, complement signaling via C5aR1 prevents active Treg induction by activating the PI3K-AKT-mTOR pathway. LIF enhances the expression of FOXP3 and opposes Th17 polarization caused by IL-6. Natural products such as epigallocatechin-3-gallate, curcumin, and rosmarinic acid regulate pathways by inhibiting DNA methyltransferases, the complement cascade, and JAK-STAT signaling. Bromelain and cineole have clinical evidence in favor of efficacy in acute sinusitis, and other compounds are showing emerging evidence. The FOXP3-C5aR1-LIF axis is a mechanistic therapeutic target that is largely overlooked by the current biologics. Natural compounds offer potential benefits, including multi-target activity, favorable safety profiles, and the ability to modulate the upstream immune system. Phenotype-based CRS populations should be studied in well-designed trials, bioavailability formulations should be optimized, and synergistic combinations should be systematically explored.