We found that PJ34 disrupted the interaction between the SARS-CoV-2 N protein and Dicer, XPO5, SRSF3, and hnRNPA3 and relieved N protein-induced downregulation of these proteins, thereby alleviating the N protein-induced DNA damage and proteotoxic stress and ultimately mitigating N protein-induced pneumonia. Here, XPO5 is linked to pneumonia.