Piezo2 Mediates a Vicious Cycle of “Mechanical Homeostasis Imbalance—Inflammation” in Sensory Nerves and the Cartilage Endplate

ABSTRACT Low back pain is a global health problem. Discogenic low back pain, the most common type of low back pain, is closely related to cartilage endplate (CEP) degeneration and inflammation. In this study, by constructing a rat model of lumbar spine instability (LSI) and combining biomechanical analysis with molecular biology techniques, we revealed the central role of the mechanosensitive channel Piezo2 in the vicious cycle of discogenic low back pain. The results revealed that abnormal mechanical stress triggers calcium influx and promotes CGRP release by activating Piezo2 in the dorsal root ganglion (DRG). CGRP synergizes with mechanical force to activate the IKKβ/NF‐κB pathway in CEP cells via the receptor RAMP1, which induces the secretion of IL‐6 and IL‐1β, and further sensitizes DRG neurons, forming a positive feedback loop. Macrophage depletion did not alleviate pain/inflammation. Targeted inhibition of Piezo2 (with AAV‐shPiezo2 gene silencing or omega‐3 fatty acids) or blockade of CGRP signaling (with Rimegepant) significantly alleviated pain‐related behaviors, suppressed inflammation, and delayed CEP degeneration. This study elucidated a novel mechanism by which mechanical‒neuroinflammatory interactions drive the progression of discogenic low back pain and provided a theoretical basis for the development of multitargeted combination treatment strategies.