Ribonucleotide reductase regulatory subunit M2 as a macromolecular target bridging small cell lung cancer progression and SARS-CoV-2 infection.

Small cell lung cancer (SCLC) is an aggressive malignancy with profound immunosuppression, yet its vulnerability to COVID-19 and underlying molecular mechanisms remain unclear. We integrated nationwide epidemiological data, transcriptomic profiling, molecular docking, and in vitro validation to investigate this relationship. Analysis of CDC WONDER (1999-2021) revealed a reversal of the long-term decline in the mortality-to-incidence ratio during 2019-2021, while SEER data demonstrated that SCLC patients had the highest COVID-19-specific mortality among lung cancer subtypes, with multivariate Cox regression confirming SCLC as an independent risk factor (HR = 2.99, P < 0.05). Transcriptomic integration identified 64 shared differentially expressed genes enriched in immune-inflammatory and interferon pathways, with RRM2, UBE2C, and CCNB2 consistently upregulated. Experimental validation confirmed markedly elevated RRM2 expression in SCLC cells, and siRNA-mediated knockdown significantly impaired proliferation and migration (P < 0.05). Molecular docking revealed strong binding of RRM2 to SARS-CoV-2 3CLpro (-21.0 kcal/mol), while the RRM2 inhibitor COH29 exhibited superior affinity compared with Triapine and showed robust stability in molecular dynamics simulation. These findings indicate heightened vulnerability of SCLC patients to adverse COVID-19 outcomes and implicate RRM2 as a potential molecular link between aggressive tumor biology and virus-associated host susceptibility.