An Acta Pharmaceutica Sinica B study identified small‑molecule inhibitors of SARS‑CoV‑2 papain‑like protease (PLpro) and host kinase RIPK1 that, when combined, produced potent synergistic antiviral effects in a mouse COVID‑19 model. The paper reported improved virologic and pathologic outcomes versus single agents. The results support combination strategies that pair direct‑acting antivirals with host‑directed modulators to enhance efficacy and limit resistance. The preclinical synergy provides an experimental blueprint for next‑generation COVID‑19 therapeutic regimens.