Thus, our results suggest that while gemcitabine kills bladder cancer cells through apoptosis, a cytoprotective autophagy is also induced involving HMGB1-mediated JNK and ERK to counteract the cytotoxicity of gemcitabine, and intervention targeting this pathway may improve the anticancer efficacy of gemcitabine against bladder cancer. The gene discussed is MAPK8; the disease is urinary bladder cancer.