Altogether, the above results indicate that the CB1R‐Hmgcs2 axis mediates maladaptive ketogenesis in SCs following DM, resulting in a significant diversion of acetyl‐CoA, impairment of the TCA cycle, increased ROS production, mitochondrial dysfunction, and ultimately decompensated homeostasis, resulting in DPN. The gene discussed is CNR1; the disease is diabetes mellitus.