Targeting Inflammatory Cell Death: A Strategy for Discogenic Pain Relief.

Low back pain caused by intervertebral disc degeneration (IVDD) remains a major challenge in clinical management, and its underlying mechanisms have not yet been fully elucidated. Beyond apoptosis, recent studies have shown that pyroptosis, ferroptosis, and necroptosis-as key inflammatory programmed cell death pathways-actively contribute to the pathological progression of IVDD and the development of pain. Currently, effective clinical solutions for discogenic pain are still lacking. This review systematically elaborates on the mechanisms of pyroptosis, ferroptosis, and necroptosis, and explains their activation in different anatomical regions of the intervertebral disc (nucleus pulposus, annulus fibrosus, and endplate). These processes promote pain by altering the local microenvironment, such as through the release of inflammatory factors and the disruption of tissue structure. Furthermore, the article summarizes potential therapeutic strategies targeting these specific cell death pathways, including molecular inhibitors, natural compounds (eg, hesperidin, melatonin), and traditional formulations, with a focus on their prospects for alleviating IVDD-related pain by modulating core cell death mechanisms. By systematically reviewing these novel cell death mechanisms and related therapeutic strategies, this work aims to provide new insights and evidence for the clinical management of discogenic pain.