Targeting Ferroptosis Attenuates Inflammation, Fibrosis, and Mast Cell Activation in Chronic Prostatitis

Figure 9

Summary of the mechanism of ferroptosis in chronic prostatitis. Cystine is intracellular transported through system Xc^- and utilized for GSH synthesis, which is an essential cofactor of GPX4 for removing phospholipid hydroperoxides (PLOOHs). ACSL4 and LPCAT3 are involved in the esterification and incorporation process of PUFA into membrane lipid and thus served as the substrates of lipid peroxidation. Iron overload initiated the Fenton reaction to generate excessive lipid ROS, including PLOOH, through oxidizing PUFAs or PUFA-containing lipids. The excessive production of ROS and suppression of GPX4 reduced host defense against oxidative stress and thus mediated the onset of ferroptosis in prostatitis. Ferroptosis-associated cell breakdown brought the recruitment of macrophage cell, T cell, and mast cell, resulting in intensive inflammation and pain sensitization. The uncontrolled inflammatory response promotes the occurrence of oxidative damage and ferroptosis in a feedback manner and therefore causes persistent inflammation, fibrosis, and pain in patients with chronic prostatitis. NRF2 positively regulated antioxidant molecules (SLC7A11, GPX4, HO-1, etc.) to inhibit ferroptosis. Iron chelator DFO and free radical scavenger EDA prevent ferroptosis by reducing iron availability and lipid peroxidation.