Natural Antidepressants in Neuroimmunomodulation: Molecular Mechanisms, Action Targets, and Therapeutic Potential

Shimeng Lv¹Ling Hui Kong¹Ruirui Shang¹Xia Zhong²Yitong Lu¹Guangheng Zhang¹Haonan Gao¹Xin Hou³Guoqiang Li^4*Xiaowen Yu^5*

• ¹Shandong University of Traditional Chinese Medicine, Jinan, China
• ²Peking University, Beijing, China
• ³Guangzhou University of Chinese Medicine, Guangzhou, China
• ⁴Shandong Provincial Qianfoshan Hospital, Jinan, China
• ⁵Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China

Depression is a major global public health issue, yet key bottlenecks remain in understanding its pathophysiological mechanisms, which significantly hinder breakthroughs in precision treatment strategies. Recent studies have highlighted the neuroimmune system as a primary pathogenic contributor to the onset and progression of depression. Meanwhile, natural products, characterized by multi-component synergy, multi-target activity, and multi-pathway regulation, have shown significant potential in regulating neuroimmunity. However, a systematic review of the role of neuroimmunity in the pathological process of depression and the therapeutic effects of natural products is still lacking. This review aims to comprehensively elucidate the core role of neuroimmunity in the pathological mechanisms of depression through literature analysis, explore in depth the molecular mechanisms and targets involved in natural product interventions, and critically evaluate the limitations and current challenges in clinical translation. Ultimately, this review provides a solid theoretical foundation and guidance for future research and the development of precision antidepressant therapies based on natural products.Recent advances in molecular biology have significantly accelerated research into the neuroimmunomodulatory mechanisms of depression, leading to a growing body of compelling evidence. Within this context, natural products have demonstrated unique and promising therapeutic potential in antidepressant strategies due to their characteristic multi-target, synergistic modulation. However, current research still faces critical challenges, including fragmented mechanistic understanding, an unclear network of action targets, and limited clinical translation. These issues severely hinder the development of novel natural antidepressants targeting neuroimmune pathways. This review aims to integrate the existing literature, systematically clarify the central role of the neuroimmune axis in the pathophysiology of depression, and summarize the molecular mechanisms by which natural compounds modulate neuroimmunity. In addition, it critically evaluates the limitations of current research. Ultimately, this review provides a theoretical foundation and offers direction for future research and the clinical translation of neuroimmune-targeted natural antidepressants.To investigate the pathological mechanisms of depression mediated by neuroimmunity and the neuro-immunomodulatory effects of natural products in treating depression, we conducted a comprehensive search of the PubMed, Web of Science, and ScienceDirect databases based on the PRISMA.