The potential role of indomethacin in COVID-19 management: A systematic review of therapeutic and mechanistic evidence.

Background: Indomethacin has been proposed as a repurposed agent for COVID-19 due to its anti-inflammatory and potential antiviral effects against coronaviruses. However, the available evidence is limited, heterogeneous, and largely indirect, with a large observational NSAID study dominating the sample size without evaluating indomethacin-specific efficacy. Methods: We conducted a PRISMA 2020-compliant systematic review registered in PROSPERO (CRD420251272994). Major databases and trial registries were searched from January 2019 to July 2025 using reproducible strategies. Eligible studies included randomized trials, observational studies, case series, and experimental investigations. Clinical and mechanistic evidence were synthesized separately, and risk of bias was assessed using RoB 2 and ROBINS-I tools. Results: Eight studies were included: two randomized trials, three observational studies, one case series, one in vitro study, and one pharmacokinetic/pharmacodynamic modeling study. The largest dataset (n = 536,423) provided indirect safety data only. Small clinical studies suggested faster symptom resolution and shorter hospitalization in mild-to-moderate cases, but findings were inconsistent and at risk of bias. Experimental studies supported antiviral mechanisms, including inhibition of viral RNA synthesis and host translation pathways. No study evaluated prophylactic use. Conclusion: Evidence for indomethacin in COVID-19 remains limited and low certainty. Safety conclusions should be cautious given incomplete reporting and known NSAID risks. Larger, well-designed randomized trials are required.