Notably, the anti-inflammatory, neuroprotective, and antidepressant effects of LIPUS are significantly attenuated by IVM, highlighting the critical role of P2X4R suppression in mediating therapeutic effects.<h4>Conclusion</h4>LIPUS mitigates LPS-induced neuroinflammation, neuronal apoptosis, and depression-like behavior by targeting microglial P2X4R and activating the BDNF/TrkB pathway. Here, P2RX4 is linked to major depressive disorder.