The GPR68-NINJ1 axis: an emerging mechano-chemical checkpoint in blood–brain barrier disruption—a hypothetical framework and therapeutic promise

The blood–brain barrier (BBB) is a critical interface whose failure is a convergent pathological feature of traumatic, ischemic, and neurodegenerative neurological diseases. Current paradigms often overlook the synergistic interplay between mechanical forces and biochemical cues, such as acidosis, that drive BBB disruption. This perspective synthesizes groundbreaking, yet largely independent, discoveries on two key molecules: GPR68 (OGR1), a proton-sensing GPCR with unique millisecond-level mechanosensitivity to shear stress, and NINJ1, a recently defined executor of plasma membrane rupture during lytic cell death. We propose a testable novel hypothesis: that these proteins form a functional “GPR68-NINJ1 axis,” creating a self-amplifying mechano-chemical circuit that initiates and exacerbates BBB breakdown. We detail the molecular logic of this axis—from GPR68’s sensing of pathological acidosis (pH ≤ 6.4) and shear stress to NINJ1’s oligomerization and DAMP release—and explore its potential role in unifying the pathophysiology of diverse disorders like TBI, stroke, MS, and AD. Finally, we translate this framework into a roadmap for future research and therapeutic intervention, discussing targeted inhibitors, precision chronotherapy, and the critical experiments needed to validate this emerging paradigm.