All these results suggest that naphplatin can promote HMGB1 cytosolic translocation and inhibits Beclin-1-PI3K-III core complex formation through the MEK/ERK1/2 pathway to modulate CTSL and autophagy-lysosome function, which therefore enhances the sensitivity of colorectal cancer to naphplatin. Here, MAPK3 is linked to colorectal cancer.