Davunetide promotes structural and functional recovery of the injured spinal cord by promoting autophagy.

Inflammatory cytokines, a class of low−molecular−weight proteins that includes interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), and chemokines, function as critical modulators of immune responses (–). Dysregulated cytokine release underlies both chronic autoimmune disorders, such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, and acute conditions like sepsis and COVID−19 associated cytokine storms (CS) (–). Among these key pathogenic mediators, IL−6, IL−1β, TNF−α, and IFN−γ play pivotal roles (–). IL-6 is a multifunctional cytokine that displays both pro-inflammatory and anti-inflammatory properties, a duality primarily arising from its two distinct signaling pathways (–). When IL-6 binds to membrane-bound IL-6 receptor (mIL-6R), it initiates the classical signaling pathway. This pathway involves gp130 homodimerization and primarily activates hepatocytes and specific immune cells, leading to the synthesis of acute-phase proteins, differentiation of regulatory T cells, and promotion of tissue repair. Thus, the classical pathway is generally regarded as anti-inflammatory and homeostatic in function (). Conversely, IL-6 binds to soluble IL-6 receptor (sIL-6R), which is generated via proteolytic cleavage (primarily by ADAM17) or alternative splicing. The IL-6/sIL-6R complex then activates any cell expressing gp130 (e.g., endothelial, epithelial, and fibroblast cells) in a process termed trans-signaling, which is the main pathway driving chronic inflammation and tissue damage (). As an upstream regulator of the JAK/STAT pathway, IL−6 amplifies inflammation by inducing the expression of downstream factors such as IL−1β, TNF−α, IFN−γ, and IL−17 (–). Clinically, elevated IL−6 levels correlate with disease severity. For example, levels in patients with acute respiratory distress syndrome (ARDS) exceed 1000 pg/mL, which starkly contrasts with concentrations in healthy individuals (1–5 pg/mL) (, ). Clinically, IL−6 is neutralized by antibodies (tocilizumab/siltuximab) or soluble receptor constructs (–). Hemoadsorption is preferred when rapid removal is required, when neutralizing antibodies fail due to excessive antigen burden, or when multi−cytokine clearance is desired (e.g., septic shock, CAR−T therapy). Consequently, IL−6 serves as both a biomarker for CS−related severity and a therapeutic target. This dual role drives the demand for efficient IL−6 removal strategies (–).