Cortistatin Consistently Modulates Neuroimmune and Inflammatory Pathways Across Diverse Preclinical Disease Models

Chronic inflammatory diseases represent a significant global health burden, often leading to progressive tissue damage despite current therapeutic interventions. Many existing treatments struggle to achieve sustained control of inflammation, highlighting a critical need for novel approaches. Cortistatin (CST), an endogenous neuropeptide structurally related to somatostatin, has emerged as a promising candidate due to its multifunctional role in regulating neuroimmune and immunometabolic pathways, offering a potential avenue to address this therapeutic gap.

This scoping review, conducted according to PRISMA-ScR guidelines, systematically mapped and synthesized preclinical evidence on Cortistatin's biological roles and therapeutic potential. Researchers performed a comprehensive literature search, identifying 31 preclinical studies published between 2006 and 2025. These studies evaluated either Cortistatin administration or the effects of cortistatin deficiency across a wide range of experimental disease models, including neurodegenerative, autoimmune, cardiovascular, fibrotic, and musculoskeletal conditions, to assess its impact on inflammatory processes and outcomes.

The review found that Cortistatin consistently demonstrated protective effects across all 31 preclinical studies, despite substantial heterogeneity in disease models. CST administration consistently reduced pro-inflammatory cytokine production, attenuated tissue damage, and improved functional outcomes and survival. Mechanistically, Cortistatin modulated key inflammatory pathways, including NF-κB signaling and NLRP3 inflammasome activation. It also suppressed Th1 and Th17 immune responses while promoting regulatory T cell expansion. These effects were mediated through interactions with specific receptors, notably somatostatin receptors, GHSR1a, and MrgX2. Emerging translational strategies, such as peptide analogues, protease-activated prodrugs, and nanoparticle-based delivery systems, have shown improved pharmacokinetic stability and therapeutic efficacy in experimental models. > Cortistatin consistently reduced pro-inflammatory cytokine production, attenuated tissue damage, and improved functional outcomes and survival across 31 diverse preclinical studies.