Liraglutide treats depression through a novel PI3K/Nrf2/HMGB1 anti-inflammatory pathway in microglia | Research

The takeaway

Liraglutide reduces depressive behaviors in chronic stress mice by activating PI3K/AKT→Nrf2→HMGB1 pathway, reducing microglial neuroinflammation and oxidative stress, with in vitro confirmation of BV2 microglia-to-HT22 neuron protection.

Novel antidepressant mechanism
Liraglutide acts through PI3K/AKT → Nrf2 → HMGB1 downregulation to reduce microglial neuroinflammation—a previously unknown antidepressant mechanism for GLP-1 drugs

What the researchers found

Liraglutide: reduced depressive behaviors in chronic stress mice. Mechanism: PI3K/AKT → Nrf2 activation → HMGB1 downregulation → reduced microglial inflammation + oxidative stress. In vitro: BV2-HT22 co-culture confirmed neuroprotection. Novel pathway for antidepressant mechanism.

Why it matters

Depression affects 300 million people with many non-responders to current treatments. Discovering a novel anti-inflammatory mechanism for liraglutide's antidepressant effects could open new therapeutic approaches, especially for inflammation-driven depression.

How the study worked

Network pharmacology target prediction. In vivo chronic stress depression mouse model. In vitro BV2 microglia/HT22 neuron co-culture. Western blot, behavioral testing, inflammatory markers.

What this study cannot tell us

Mouse model. Network pharmacology predictions need broader validation. Single GLP-1 drug tested. Chronic stress model is one of several depression models. Translation to human depression uncertain.

How to read the evidence

Comprehensive preclinical study combining network pharmacology, in vivo behavior, and in vitro mechanism. Novel pathway well-demonstrated.

When this study was published

Published in 2025.

The bigger picture

This adds a specific molecular mechanism to the growing evidence for GLP-1 drugs as antidepressants. The PI3K/Nrf2/HMGB1 pathway connects metabolic signaling with neuroinflammation—a bridge between diabetes and depression biology.

Questions still open

Would targeting HMGB1 directly replicate liraglutide's antidepressant effect?
Is the PI3K/Nrf2 pathway engaged by other GLP-1 drugs?
Could this mechanism explain reduced depression in diabetic patients on GLP-1 therapy?

Common questions

Can a diabetes drug treat depression?

This study shows liraglutide reduces depressive behaviors in mice through a specific anti-inflammatory mechanism: it activates Nrf2 (an antioxidant master switch) which calms brain inflammation by reducing HMGB1. This is a completely new explanation for why GLP-1 drugs may improve mood beyond their metabolic effects.

How does inflammation relate to depression?

Brain inflammation (neuroinflammation) from overactive microglia contributes to depression by damaging neurons and disrupting mood-regulating circuits. Liraglutide calms these inflammatory microglia through the PI3K/Nrf2/HMGB1 pathway, protecting neurons and reducing depressive symptoms in this mouse study.

Read the original research

Exploring the Effect and Mechanism of Liraglutide in Treating Depression Based on Network Pharmacology and Experimental Analysis.

Journal of cellular and molecular medicine, 29(11), e70630

View on PubMed ↗Publisher’s paper ↗

Citation

Sun, Jiangjin; Fu, Xiying; Liu, Yaqi; Wang, Tian; Zhao, Xing; Cui, Ranji; Yang, Wei. (2025). Exploring the Effect and Mechanism of Liraglutide in Treating Depression Based on Network Pharmacology and Experimental Analysis.. Journal of cellular and molecular medicine, 29(11), e70630. https://doi.org/10.1111/jcmm.70630