The Kindlin protein family, consisting of Kindlin-1, Kindlin-2, and Kindlin-3, is crucial in cellular physiology and pathology. Traditionally recognized as essential co-activators of integrins, Kindlins regulate integrin-dependent adhesion, migration, and signal transduction across diverse cell types. Recent advances, however, have revealed that Kindlins extend beyond integrin activation, participating in non-integrin-dependent signaling pathways and transcriptional regulation. This review provides a comprehensive summary of structural, physiological, and pathological roles of Kindlins, integrating their classical integrin-dependent and emerging integrin-independent functions. In this review, we a) offer a comprehensive overview of the structural and functional roles of Kindlin proteins across various organ systems; b) highlight their integrin-independent signaling functions and exact regulatory mechanisms; c) discuss their contributions to pathologies and explore the potential of Kindlins as biomarkers and therapeutic targets.

Intervertebral disc (IVD) degeneration (IVDD) is the main cause of low back pain with major social and economic burdens; however, its underlying molecular mechanisms remain poorly defined. Here we show that the focal adhesion protein Kindlin-2 is highly expressed in the nucleus pulposus (NP), but not in the anulus fibrosus and the cartilaginous endplates, in the IVD tissues. Expression of Kindlin-2 is drastically decreased in NP cells in aged mice and severe IVDD patients. Inducible deletion of Kindlin-2 in NP cells in adult mice causes spontaneous and striking IVDD-like phenotypes in lumbar IVDs and largely accelerates progression of coccygeal IVDD in the presence of abnormal mechanical stress. Kindlin-2 loss activates Nlrp3 inflammasome and stimulates expression of IL-1β in NP cells, which in turn downregulates Kindlin-2. This vicious cycle promotes extracellular matrix (ECM) catabolism and NP cell apoptosis. Furthermore, abnormal mechanical stress reduces expression of Kindlin-2, which exacerbates Nlrp3 inflammasome activation, cell apoptosis, and ECM catabolism in NP cells caused by Kindlin-2 deficiency. In vivo blocking Nlrp3 inflammasome activation prevents IVDD progression induced by Kindlin-2 loss and abnormal mechanical stress. Of translational significance, adeno-associated virus-mediated overexpression of Kindlin-2 inhibits ECM catabolism and cell apoptosis in primary human NP cells in vitro and alleviates coccygeal IVDD progression caused by mechanical stress in rat. Collectively, we establish critical roles of Kindlin-2 in inhibiting Nlrp3 inflammasome activation and maintaining integrity of the IVD homeostasis and define a novel target for the prevention and treatment of IVDD.