The inflammatory/fibrotic axis across organs: myelofibrosis as a model of reversibility.

Current therapeutic interventions for spinal cord injury (SCI) demonstrate limited efficacy. This condition induces severe and permanent physical, neurological, and psychological impairments, substantially diminishing quality of life [,]. The global increase in SCI incidence imposes considerable societal and economic burdens on healthcare systems and social services [, , ]. SCI classification distinguishes between traumatic and non-traumatic etiologies [], with traumatic SCI predominating. Primary mechanical trauma typically results from events like falls, motor vehicle accidents, or sports injuries, causing immediate cellular death, blood-spinal cord barrier disruption, and extracellular matrix degradation. These primary effects are compounded by secondary pathological processes—including inflammation, oxidative stress, and extensive nerve damage—that critically drive injury progression and severity, thereby hindering recovery [, , ]. Arachidonic acid (AA) serves as a key signaling molecule in cellular injury responses []. Exogeneous source of AA is from animal food and from vegetable oil linolic acid and also from lipid droplet []. Endogeneous AA is stored within the phospholipid bilayer, and is released during cellular stress or damage via cytosolic phospholipase A2 （cPLA2) activity []. Metabolism of free AA occurs primarily through four enzymatic pathways: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) and the endocannabinoids pathway []. Non enzymatic pathway is the oxidation of free AA in the ROS-rich microenvironment [] (). AA metabolites are involved in a wide range of physiological processes, including inflammation, immune response regulation, and tissue remodeling []. Elevated levels of AA and its metabolites characterize the acute phase of SCI, influencing inflammatory regulation and initiating repair mechanisms[]. While the initial inflammatory response mediated by AA derivatives is essential for debris clearance and tissue repair, sustained inflammation paradoxically promotes chronic tissue damage, exacerbating neural degeneration and compromising functional recovery []. The interplay between AA metabolism and neuroinflammation has garnered significant interest for its potential role in SCI pathogenesis. Evidence indicates that dysregulation of AA-derived bioactive mediators exacerbates the inflammatory cascade and amplifies secondary injury mechanisms post-SCI. In this review, we comprehensively evaluate the mechanisms that regulate AA metabolism in SCI and the AA-derived bioactive mediators which contribute to the injury. Furthermore, we evaluate potential therapeutic strategies aimed at modulating AA metabolism to mitigate its detrimental effects and improve recovery outcomes.