Targeting JAK/STAT signaling pathway by curcumin: implications for spinal cord injury neuroprotection

Spinal cord injury (SCI) has emerged as a significant worldwide health burden, featuring a biphasic pathological progression comprising initial mechanical trauma followed by progressive secondary degeneration driven by inflammatory processes. A key orchestrator of this secondary phase is the JAK/STAT signaling pathway, whose dysregulated activation exacerbates neuronal damage and impairs tissue repair. Mounting evidence implicates JAK/STAT components in diverse aspects of SCI pathology, including pro-inflammatory cytokine expression, astrocyte reactivity, autophagy, and axonal regeneration. Curcumin, a bioactive polyphenol derived from Curcuma longa, has demonstrated multi-target neuroprotective properties in various CNS disorders. However, its specific mechanisms of action on the JAK/STAT pathway in SCI remain inadequately elucidated. This review provides a mechanistic synthesis of current preclinical studies examining curcumin's modulatory effects on JAK/STAT signaling in SCI models. In particular, we highlight four key regulatory mechanisms: (i) inhibition of aberrant JAK2 and STAT1/3 phosphorylation, (ii) suppression of STAT3 and NF-κB nuclear translocation, (iii) activation of the JAK1/STAT6 axis via IL-4-mediated M2 microglial polarization, and (iv) upregulation of endogenous inhibitors such as SOCS1 and PIAS3. Unlike previous reviews, this article offers a targeted analysis of curcumin's interaction with distinct nodes of the JAK/STAT axis, emphasizing its dual role in dampening pathological signaling while supporting reparative STAT6 activation. By integrating cellular, molecular, and behavioral findings, we position curcumin as a promising phytotherapeutic agent for SCI. Furthermore, we identify critical gaps in mechanistic understanding and pharmacokinetic optimization that must be addressed to enable clinical translation. Overall, this review provides a comprehensive framework for advancing curcumin as a multi-target therapeutic strategy aimed at precise immunomodulation via JAK/STAT signaling in SCI.