Old drug with new application: spironolactone suppresses Panx 1-mediated Ca2+ influx to attenuate inflammation-driven neutral lipid accumulation in early atherosclerosis.
Yang Y, Gu T, et al. • Inflammation research : official journal of the European Histamine Research Society ... [et al.] • 2026
Spironolactone mitigates early atherosclerosis by reducing endothelial activation and attenuating inflammation-driven intracellular neutral lipid accumulation via suppression of the Panx1/Ca2+/NF-κB signaling axis.
Key Findings
Results
Spironolactone (SP) significantly ameliorated plasma biochemical parameters, mitigated aortic inflammation, and reduced lipid deposition in an early atherosclerosis mouse model.
In vivo experiments used ApoE-/- mice fed a high-fat diet as an early atherosclerosis model
SP administration reduced endothelial activation and alleviated endothelium damage in vivo
SP reduced aortic inflammation and subendothelial lipid deposition in the early atherosclerosis model
SP improved plasma biochemical parameters associated with cardiovascular risk
Results
Non-targeted metabolomic profiling revealed that spironolactone profoundly remodeled the plasma metabolome, indicating systemic metabolic restoration.
Non-targeted metabolomic profiling was performed on plasma samples from the ApoE-/- mouse model
SP treatment produced significant changes in the plasma metabolome compared to untreated atherosclerotic mice
The metabolomic changes were interpreted as reflecting systemic metabolic restoration beyond lipid-lowering effects
This finding suggests SP's protective effects extend to broad systemic metabolic pathways
Results
Spironolactone reversed TNF-α-induced endothelial cell activation and attenuated oleic acid-induced neutral lipid accumulation in human umbilical vein endothelial cells (HUVECs) in vitro.
In vitro experiments were conducted using human umbilical vein endothelial cells (HUVECs)
TNF-α was used to induce endothelial cell activation and inflammation
Oleic acid (OA) was used to induce intracellular neutral lipid accumulation in endothelial cells
SP treatment reversed both TNF-α-induced activation and OA-induced lipid accumulation
Results
Pannexin 1 (Panx1) expression levels did not differ significantly between normal and abnormal endothelial function in atherosclerosis mouse models or clinical subjects.
Panx1 expression was assessed in both in vivo atherosclerosis mouse models and clinical subjects
No significant difference in Panx1 expression was observed between normal and dysfunctional endothelium
This finding indicates SP's protective effects are mediated through functional inhibition of Panx1 channels rather than changes in Panx1 protein expression levels
SP inhibited TNF-α-induced Panx1 expression while also blocking the functional opening of Panx1 channels
Results
Spironolactone inhibited TNF-α-induced Panx1 expression and blocked the functional opening of Panx1 channels, thereby preventing subsequent intracellular Ca2+ influx.
SP acts as a pharmacological inhibitor of pannexin 1 (Panx1) channels in endothelial cells
Attenuation of intracellular Ca2+ overload was identified as essential for SP's protective effects against endothelial dysfunction
Ca2+ overload prevention was also essential for protection against inflammation-mediated oleic acid-induced intracellular neutral lipid accumulation
Results
Spironolactone suppresses NF-κB signaling activation by inhibiting Panx1-dependent intracellular Ca2+ rise, revealing a mechanistic Panx1/Ca2+/NF-κB axis that regulates inflammation-driven intracellular neutral lipid accumulation.
A Panx1/Ca2+/NF-κB signaling axis was identified as the mechanistic pathway regulating inflammation-driven neutral lipid accumulation
SP's inhibition of Panx1 channel function blocked Ca2+ influx, which in turn suppressed NF-κB signaling activation
NF-κB signaling suppression was linked to reduced inflammation-mediated intracellular neutral lipid accumulation
This axis connects endothelial inflammation to lipid accumulation in early atherosclerosis
Discussion
Pannexin 1 (Panx1) is identified as a key mediator in endothelial cells through which spironolactone ameliorates vascular inflammation and sustains endothelial cell function in early atherosclerosis.
Panx1 on endothelial cells was established as a promising therapeutic target for early vascular intervention in atherosclerosis
SP's pharmacological inhibition of Panx1 mediated its protective effects on endothelial function
SP was proposed as a potential candidate for prevention of atherosclerotic cardiovascular disease based on this mechanism
The study framed Panx1 as a pivotal mediator of the inflammatory response in endothelial cells during early atherosclerosis
What This Means
This research suggests that spironolactone, a medication already widely used for conditions like high blood pressure and heart failure, may have an additional benefit in preventing early-stage atherosclerosis (the buildup of plaques in artery walls). The study found that spironolactone works by blocking a protein channel called Pannexin 1 (Panx1) in the cells lining blood vessels. When these cells are inflamed, Panx1 channels open and allow calcium to flood into the cells, which triggers a chain reaction that activates inflammatory signals (NF-κB) and causes fat droplets to accumulate inside the cells. Spironolactone interrupts this process by blocking Panx1, reducing calcium overload, dampening inflammation, and preventing fat buildup—all early steps in atherosclerosis development.
The researchers demonstrated these effects both in mice with early atherosclerosis fed a high-fat diet and in laboratory experiments with human blood vessel cells. In mice, spironolactone improved blood chemistry, reduced inflammation in the aorta, and decreased lipid deposits. Interestingly, the amount of Panx1 protein present in blood vessel cells was the same whether those cells were healthy or diseased—meaning the drug works by blocking how the channel functions, not by changing how much of it exists. Metabolic profiling also showed that spironolactone broadly restored metabolic balance throughout the body in treated mice.
This research suggests that Panx1 could be a valuable new target for treating early cardiovascular disease, and that spironolactone—an inexpensive, well-established drug—might be repurposed to specifically address the inflammation-driven component of atherosclerosis that current lipid-lowering drugs do not fully tackle. Further clinical investigation would be needed to determine whether these findings translate to benefits in humans with early-stage arterial disease.
Yang Y, Gu T, Zheng M, Huang Q, Lu J, Chen J, et al.. (2026). Old drug with new application: spironolactone suppresses Panx 1-mediated Ca2+ influx to attenuate inflammation-driven neutral lipid accumulation in early atherosclerosis.. Inflammation research : official journal of the European Histamine Research Society ... [et al.]. https://doi.org/10.1007/s00011-026-02361-z