MCL1 promotes endothelial senescence and atherosclerosis through a metabolic-epigenetic axis involving glycolytic reprogramming, lactate accumulation, and H4K12 lactylation-associated P21 upregulation.
Key Findings
Results
MCL1 expression was significantly upregulated in atherosclerotic plaques and senescent endothelial cells across multiple models.
MCL1 upregulation was validated in human carotid atherosclerotic plaques, ApoE-/- mice, and multiple EC senescence models
Primary senescence model used was HRASG12V-induced senescent human umbilical vein endothelial cells (HUVECs)
MCL1 was identified as a candidate senescence regulator through integrative bioinformatics analysis
Elevated MCL1 expression correlated with senescent endothelial cell accumulation in atherosclerotic tissue
Results
MCL1 knockdown attenuated endothelial cell senescence markers and restored cell proliferation, while MCL1 overexpression exacerbated senescence.
MCL1 knockdown suppressed senescence markers SA-β-gal and P21
MCL1 knockdown suppressed the senescence-associated secretory phenotype (SASP)
MCL1 knockdown restored cell proliferation in senescent HUVECs
MCL1 overexpression exacerbated EC senescence in loss- and gain-of-function assays performed in HUVECs
Results
MCL1 promoted glycolytic reprogramming and intracellular lactate accumulation in endothelial cells.
Glycolytic reprogramming was assessed using Seahorse extracellular flux analysis and lactate measurements
This metabolic shift represented a key mechanistic step linking MCL1 activity to downstream epigenetic changes
Lactate produced through MCL1-driven glycolysis served as an epigenetic substrate
Results
MCL1-driven lactate accumulation served as an epigenetic substrate for histone H4K12 lactylation (H4K12la), which enriched at the CDKN1A (P21) promoter and correlated with P21 transcription.
H4K12 lactylation (H4K12la) was identified as the specific epigenetic modification driven by MCL1-associated lactate
CUT&Tag sequencing was used to identify H4K12la enrichment at the CDKN1A (P21) promoter
Co-IP experiments were used to explore the mechanistic interactions
H4K12la enrichment at the CDKN1A promoter correlated with increased P21 transcription
This represented a direct metabolic-to-epigenetic mechanism linking glycolysis to senescence gene expression
Results
AAV-mediated MCL1 silencing in vivo reduced vascular H4K12la levels, alleviated vascular senescence, and substantially constrained atherosclerotic lesion areas.
In vivo experiments used AAV-mediated MCL1 knockdown in high-fat diet-fed ApoE-/- mice
MCL1 silencing effectively reduced vascular H4K12la levels in vivo
MCL1 silencing alleviated vascular senescence in the atherosclerosis mouse model
MCL1 silencing substantially constrained atherosclerotic lesion areas
These findings demonstrated the therapeutic potential of targeting MCL1 in atherosclerosis
Discussion
The study identified a complete MCL1→glycolytic reprogramming→lactate accumulation→H4K12la→P21 upregulation mechanistic axis driving endothelial senescence and atherosclerosis.
MCL1 acts as a pivotal regulator operating through a metabolic-epigenetic mechanism
The pathway sequentially connects MCL1 activity to glycolytic reprogramming, lactate accumulation, H4K12 lactylation, and CDKN1A/P21 transcription
Authors propose that targeting the MCL1-associated pathway may represent a potential therapeutic strategy for atherosclerosis
The findings link the anti-apoptotic protein MCL1 to a non-canonical role in metabolic and epigenetic reprogramming during senescence
What This Means
This research suggests that a protein called MCL1, previously known for its role in preventing cell death, plays an unexpected and harmful role in blood vessel aging and the development of atherosclerosis (hardening of the arteries). The study found that MCL1 levels are elevated in fatty plaques from human arteries and in aging endothelial cells (the cells lining blood vessels). When MCL1 is active, it causes these cells to shift their energy metabolism toward a process called glycolysis, which produces excess lactate as a byproduct. This excess lactate then acts as a chemical tag that gets added to DNA-packaging proteins (histones), specifically at a site called H4K12, in a modification called 'lactylation.' This epigenetic tag activates a key aging gene called P21, pushing cells into a state of permanent growth arrest called senescence.
The study demonstrated this mechanism using both cell culture experiments and a mouse model of atherosclerosis. When researchers used gene therapy (AAV vectors) to silence MCL1 in mice fed a high-fat diet, the mice showed reduced vascular aging markers, lower levels of the H4K12 lactylation mark, and smaller atherosclerotic plaques in their arteries. These findings connect three major biological processes — metabolic reprogramming, epigenetic modification, and cellular senescence — into a single pathway driven by MCL1.
This research suggests that the MCL1-driven pathway could be a target for new treatments aimed at slowing or reversing atherosclerosis by reducing endothelial cell senescence. The discovery that lactate, long considered a simple metabolic waste product, can drive harmful epigenetic changes in blood vessel cells adds a new dimension to our understanding of how diet-related metabolic stress contributes to cardiovascular disease.
Li Y, Li L, Gao H, Gao Y, Wu W, Fan L. (2026). MCL1 Promotes Endothelial Senescence and Atherosclerosis via Glycolytic Reprogramming-Induced H4K12 Lactylation.. International journal of molecular sciences. https://doi.org/10.3390/ijms27167392