The remarkable ability of the heart to maintain cellular homeostasis throughout life relies on efficient quality control mechanisms, in which lysosomes play a central role by ensuring the degradation and recycling of cellular components^[1]. These processes become critical during pathological stress, when a sustained increase in workload triggers cardiomyocyte hypertrophy and imposes major demands on cellular quality control and metabolic systems^[2]. Beyond their traditional degradative function, lysosomes have emerged as dynamic signaling and metabolic hubs that coordinate multiple cellular stress responses^[3]. Understanding how lysosome-centered networks contribute to cardiac adaptation may therefore provide new insights into the transition from hypertrophy to heart failure (HF).

A major regulator of lysosomal function is the basic helix-loop-helix leucine zipper transcription factor EB (TFEB) that belongs to the family of the microphthalmia/transcription factor E^[4]. TFEB activity is regulated by its abundance, its shuttling to the nucleus, and its capacity to bind to the promoters of target genes. Being highly sensitive to nutritional status and organelle damage, TFEB regulates important functions such as lysosomal biogenesis, autophagy, and exocytosis.

Early studies investigating TFEB’s role in the heart employed overexpression strategies to restore its function, as TFEB protein expression and/or nuclear translocation were impaired in various stress models. Through gene-targeted therapy, increasing TFEB expression in the heart protected against cardiac injury by improving lysosomal function and autophagic flux in amyloid light-chain (AL) amyloidosis, oxidative stress, and doxorubicin cardiotoxicity^[5-7]. While these studies demonstrated a beneficial role of cardiac TFEB overexpression, conflicting results were later obtained in the context of pressure overload. Whereas moderate TFEB overexpression (≈ 2-fold) was protective, high overexpression (≈ 8-fold) was deleterious during the transition from hypertrophy to HF^[8,9]. Excessive and uncontrolled autophagy activation or non-canonical TFEB function might underlie the detrimental cardiac effects observed with high TFEB overexpression^[8]. These findings highlight the importance of finely tuned TFEB activity. However, all studies relied on gain-of-function approaches, leaving the endogenous role of TFEB in the stressed heart unexplored.

The new study published in Circulation Research by Daou et al. employed, for the first time, a cardiomyocyte-specific TFEB knockout mouse model (CTKO) to study pressure overload-induced HF^[10]. Contrary to previous studies, the authors found that TFEB expression was transiently upregulated in the early stages of cardiac hypertrophy. In CTKO mice, transverse aortic constriction (TAC) surgery led to exaggerated hypertrophic growth, rapid transition to HF, and increased mortality compared to wild-type (WT) mice. As expected, CTKO mice failed to increase the expression of lysosomal markers in response to TAC, leading to an accumulation of LC3-II and ubiquitinated proteins, which confirms the importance of TFEB in coordinating the autophagy-lysosome pathway and proteotoxic stress. Having observed blunted phosphorylation of AMP-activated protein kinase alpha (AMPKα) in CTKO mice, Daou et al. showed that metformin, an activator of AMPKα, prevented excessive hypertrophy in TAC mice but failed to rescue lysosomal deficiency or ventricular dysfunction^[10]. To investigate the mechanisms linking TFEB deletion to ventricular dysfunction, the authors performed proteomic and transcriptomic analyses in CTKO TAC hearts. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), the master regulator of mitochondrial biogenesis and energy metabolism, was markedly downregulated, together with broad alterations in mitochondrial gene programs and function.

This study by Daou et al. provides important insights into how TFEB coordinates the cardiac response to hypertrophic stress^[10]. Their findings support a model in which TFEB engages distinct but interconnected adaptive programs: lysosomal capacity and AMP-activated protein kinase (AMPK) signaling restrain hypertrophic growth, whereas mitochondrial metabolism sustains cardiac function [Figure 1].

The authors identified a previously unrecognized TFEB-AMPK axis, opening an interesting mechanistic avenue. While AMPK is known as a regulator of TFEB activity through a phosphorylation-dependent mechanism^[4], the present study suggests a reciprocal relationship, as TFEB deletion markedly reduced AMPKα phosphorylation in TAC hearts. However, whether lysosomal dysfunction contributes to blunted AMPK activation in CTKO hearts remains to be determined, as does the potential involvement of additional AMPK-independent mechanisms in restraining hypertrophic growth. Indeed, the rescue achieved with metformin supports a role for AMPK in limiting hypertrophy, while its pleiotropic actions leave room for additional pathways linking TFEB/lysosome to metabolic adaptation and cardiac stress response^[11]. For example, whether metformin modulates mitochondrial biogenesis and function in CTKO TFEB hearts after TAC has not been evaluated in the present study.

Another important discovery is that TFEB regulates mitochondrial function. Previous studies demonstrated direct transcriptional control of PGC-1α by TFEB^[12], and Daou et al. identified selective regulation of the PGC-1α-b isoform, supporting a direct TFEB-driven mitochondrial program^[10]. Alternatively, enhanced lysosomal function may preserve mitochondrial homeostasis by promoting autophagy/mitophagy and mitochondrial quality control^[13]. These mechanisms, however, are not mutually exclusive and may act in concert to preserve mitochondrial function. One way to disentangle their respective contributions would be to improve lysosomal function independently of TFEB. Lysosome-acidifying nanoparticles, which directly restore lysosomal function and improve mitochondrial homeostasis^[14], provide one example of such an approach. Comparing TFEB-independent lysosomal rescue with direct TFEB activation could therefore help define the relative contributions of lysosome-mediated and direct transcriptional mechanisms to mitochondrial protection.

Overall, these findings position TFEB as a compelling therapeutic target at the crossroads of several major adaptive pathways in the heart. By coordinating lysosomal, metabolic, and mitochondrial adaptation, TFEB offers the possibility of simultaneously enhancing multiple aspects of cardiac stress resilience. The growing repertoire of pharmacological strategies capable of enhancing TFEB activity, including natural compounds^[15,16], cardiac glycosides^[17], and synthetic small molecules^[18], further strengthens its translational potential. However, TFEB activation must be finely tuned, as excessive overexpression can be detrimental. The magnitude, duration, and cellular context of TFEB may ultimately shape the adaptive programs engaged, emphasizing the need to tailor TFEB-targeting strategies to distinct pathological settings.