Targeting Transcription Factor EB for Cardiac Hypertrophy: From Mechanisms to Potential Clinical Application

心脏肥大是心肌细胞对压力或容积超负荷的代偿性反应，长期持续可进展为心力衰竭。转录因子EB (transcription factor EB, TFEB)作为自噬–溶酶体通路(autophagy-lysosome pathway, ALP)的主调控因子，通过维持蛋白质稳态和线粒体质量控制，在抑制心脏肥大中发挥关键保护作用。然而，病理应激条件下，E3连接酶适配体SPOP被p300转录激活，通过介导TFEB的K48链泛素化降解，导致自噬流阻断与溶酶体功能衰竭，从而推动心脏从代偿性肥大向失代偿性心力衰竭转变。该p300‑SPOP‑TFEB信号轴的阐明揭示了心脏肥大中TFEB功能缺失的上游机制，但其致病作用目前主要在压力超负荷模型中证实，在其他病因及人类心脏中的普适性仍有待验证。在系统综述TFEB保护性功能、SPOP介导的TFEB降解途径及靶向该轴药理学策略的基础上，本文将SPOP‑TFEB轴纳入TFEB多层级调控网络的宏观框架，比较不同调控通路在心脏肥大各阶段的相对重要性及其交互作用，并进一步分析TFEB激活的剂量依赖性风险、组织特异性靶向难题及转化瓶颈，以期为基于蛋白质稳态调控的心力衰竭治疗提供新的理论视角与潜在策略。 Cardiac hypertrophy is a compensatory response of cardiomyocytes to pressure or volume overload that can progress to heart failure if sustained. Transcription factor EB (TFEB), as a master regulator of the autophagy-lysosome pathway, plays a critical protective role in suppressing cardiac hypertrophy by maintaining proteostasis and mitochondrial quality control. Under pathological stress, however, the E3 ligase adaptor SPOP is transcriptionally activated by p300 and mediates K48-linked ubiquitination and degradation of TFEB, leading to autophagic flux blockade and lysosomal failure, thereby driving the transition from compensated hypertrophy to decompensated heart failure. Elucidation of this p300-SPOP-TFEB signaling axis has revealed the upstream mechanism underlying TFEB functional loss in cardiac hypertrophy. It should be noted, however, that the pathogenic role of this axis has thus far been predominantly demonstrated in pressure overload models, and its generalizability to other etiologies of cardiac hypertrophy and to the human heart remains to be established. On the basis of a systematic review of the protective functions of TFEB, the SPOP-mediated degradation pathway, and pharmacological strategies targeting this axis, this review incorporates the SPOP-TFEB axis into a broader framework of the multilayered regulatory network of TFEB, compares the relative importance and interactions of different regulatory pathways across stages of cardiac hypertrophy, and further analyzes the dose-dependent risks of TFEB activation, challenges in tissue-specific targeting, and translational bottlenecks, with the aim of providing novel theoretical perspectives and potential strategies for heart failure therapy based on proteostasis regulation.