The role of programmed cell death in diabetes mellitus-induced erectile dysfunction: from mechanisms to targeted therapy

Abstract Diabetes mellitus (DM) is a chronic metabolic disease that often leads to vascular endothelial injury and peripheral neuropathy. Erectile dysfunction (ED), a common condition in andrology, is frequently associated with DM. The incidence of diabetes mellitus-induced ED (DMED) is second only to the cardiovascular complications of diabetes. Compared to other types of ED, DMED presents with more severe symptoms, rapid progression, and notable resistance to phosphodiesterase type 5 inhibitors (PDE5is). Various forms of programmed cell death (PCD)—including apoptosis, autophagy, pyroptosis, and ferroptosis—play pivotal roles in the pathogenesis of DMED. An exacerbation of DMED is linked to critical irritants like advanced glycation end-products (AGEs) and reactive oxygen species (ROS) in the corpus cavernosum tissue. These irritants can spark anomalous activations of diverse PCDs, which damage primary corpus cavernosum cells like cavernous nerve cells, endothelial cells, and myocytes, leading to ED. Hence, we reviewed current knowledge on the mechanisms and therapeutic potential of targeting PCDs in DMED, aiming to advance strategies for enhancing erectile function.