Sensory immune and metabolic interactions in ischemic stroke and inflammatory diseases inform emerging therapeutic strategies

Sensory afferents are increasingly recognized as active participants in tissue homeostasis through interactions with vascular, immune, and parenchymal cells. In ischemic stroke, however, these pathways operate within a broader multicellular pathophysiology that also includes energy failure, excitotoxicity, oxidative stress, blood-brain barrier disruption, systemic immune responses, and multiple regulated cell-death programs [ 1 , 2 , 3 , 4 ]. This review examines how sensory receptors and neuropeptides may contribute to neuroimmune and metabolic remodeling in ischemic and inflammatory disease. TRPV1 is discussed as one component of a wider transient receptor potential channel network rather than as an exclusive upstream regulator [ 2 , 5 ]. Substance P (SP) has comparatively direct preclinical support as a mediator of neurogenic inflammation and edema after cerebral ischemia, whereas calcitonin gene-related peptide (CGRP) has context-dependent vascular and immune effects [ 6 , 7 ]. CGRP-targeted monoclonal antibodies and receptor antagonists are clinically established for migraine, but they have not been validated as stroke treatments; notably, CGRP receptor antagonism worsened ischemic outcomes in a mouse model by impairing collateral perfusion [ 8 , 9 , 10 ]. We further review mitochondrial dysfunction, SIRT1/PGC-1α signaling, lipid peroxidation, and ferroptosis as intersecting metabolic processes, while emphasizing that direct causal links from sensory signaling to these pathways in human stroke remain incompletely established [ 11 , 12 , 13 , 14 ]. The sensory-immune-metabolic framework is best viewed as a hypothesis-generating integrative model embedded within the broader neurovascular unit response to ischemia rather than as a dominant disease driver. Physical neuromodulation and ferroptosis-modulating compounds remain investigational for mechanism-specific stroke prevention. Future work should prioritize causal validation, receptor redundancy, dose and timing effects, translational pharmacology, and biomarker-stratified clinical studies before axis-directed interventions can be considered for routine stroke care.