This study shows that erinacine S, a natural compound from Lion’s Mane mushrooms, can help overcome drug resistance in colorectal cancer cells. The compound works by activating pathways that trigger cancer cell death and by modifying how genes are expressed at the molecular level. In both laboratory experiments and animal models, erinacine S successfully stopped tumor growth and killed resistant cancer cells, suggesting it could be a promising natural treatment for patients with hard-to-treat colorectal cancer.