["Acta Physiologica, Volume 242, Issue 6, June 2026. ", "\nABSTRACT\n\nAim\nChronic high‐fat diet (HFD) consumption combined with lipopolysaccharide (LPS) challenge promotes microglial hyperactivation, brain inflammation, reduced neurogenesis, and depression‐like behavior. LPS also increases adenosine triphosphate (ATP) release from immune and dying cells, activating microglia through the purinergic P2X7R receptor. However, the effects of P2X7 inhibitor on microglial hyperactivation, brain inflammation, neurogenesis, and depression‐like behavior in obese models challenged with LPS remain unclear.\n\n\nMethods\nSixty‐four male Wistar rats were fed either normal diet or HFD for 12 weeks and subsequently received an intraperitoneal (IP) injection of normal saline or LPS (500 μg/kg). LPS‐treated rats were then given saline, minocycline (45 mg/kg, twice, IP), or the P2X7R inhibitor JNJ‐55308942 (30 mg/kg, single dose, orally). Depression‐ and anxiety‐like behaviors were assessed 24 h later.\n\n\nResults\nLPS alone induced pronounced peripheral and brain inflammation, elevated circulating LPS, microglial hyperactivation, increased ATP/P2X7‐mediated neuroinflammation, excessive C1q‐mediated synaptic pruning, and mood‐related behavioral deficits. Chronic HFD additionally induced metabolic disturbances, oxidative stress, blood–brain barrier disruption, and reduced neurogenesis. Combined HFD and LPS exposures further amplified brain pathologies and the severity of mood‐related deficits. P2X7R inhibitor effectively reduced oxidative stress, suppressed ATP/P2X7‐mediated neuroinflammation, limited aberrant synaptic pruning, restored neurogenesis, and improved behaviors. Minocycline improved behavioral outcomes primarily by reducing endotoxemia and inflammation.\n\n\nConclusion\nThe comparable neuroprotection produced by JNJ‐55308942 and minocycline suggests that ATP/P2X7‐mediated neuroinflammation plays a major role in regulating brain pathologies in HFD‐fed rats, followed by LPS challenge. These findings suggest P2X7 signaling as a promising therapeutic target for depression and inflammation‐associated neuropsychiatric disorders.\n\n"]