Trap1, also known as Tumour necrosis factor receptor-associated protein 1 and Heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family mainly residing in the mitochondria [2]. As a mitochondrial molecular chaperone, it supports protein folding, maintains mitochondrial integrity, and regulates mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER) [2]. It is also involved in metabolic reprogramming, such as promoting the switch from oxidative phosphorylation to glycolysis [4].

In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), VSMC senescence and atherosclerosis were mitigated, suggesting that Trap1 drives VSMC senescence and promotes atherosclerosis via metabolic reprogramming. Mechanistically, Trap1 increases aerobic glycolysis, leading to elevated lactate production, which promotes histone H4 lysine 12 lactylation (H4K12la) by down-regulating HDAC3, and H4K12la activates SASP transcription to exacerbate VSMC senescence [1]. In ischemic retinopathy mouse models, genetic Trap1 ablation alleviates retinal pathologies via proteolytic HIF1α degradation, indicating that Trap1 is essential for blood-retinal barrier (BRB) breakdown and pathologic retinal neovascularization [3]. In primary cardiomyocytes under high glucose/palmitate conditions, Trap1 inhibits MARCH5-mediated MIC60 degradation, thereby alleviating mitochondrial dysfunction and apoptosis [5].

In conclusion, Trap1 plays crucial roles in maintaining mitochondrial function, metabolic regulation, and in multiple disease-related processes. The gene knockout and conditional knockout mouse models have significantly contributed to understanding Trap1's role in atherosclerosis, ischemic retinopathy, and diabetic cardiomyopathy, providing insights into potential therapeutic targets for these diseases.