bims-raghud 2025-01-19 papers

Issue of 2025–01–19
two papers selected by
Irene Sambri, TIGEM

Life Sci Alliance. 2025 Mar;pii: e202302259. [Epub ahead of print]8(3):

Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Milad Soleimani, Mark Duchow, Ria Goyal, Alexander Somma, Tamer S Kaoud, Kevin N Dalby, Jeanne Kowalski, S Gail Eckhardt, Carla Van Den Berg.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism. Indeed, TFEB knockdown (KD) inhibited mammosphere formation in vitro and tumor initiation/growth in vivo. These phenotypic effects were accompanied by a decline in CD44high/CD24low cells. Glycolysis inhibitor 2-deoxy-D-glucose (2-DG) induced TFEB nuclear translocation, indicative of TFEB transcriptional activity. TFEB KD blunted, whereas TFEB (S142A) augmented 2-DG-driven unfolded protein response (UPR) mediators, notably BiP/HSPA5 and CHOP. Like TFEB KD, silencing BiP/HSPA5 inhibited CSC self-renewal, suggesting that TFEB augments UPR-related survival. Further studies showed that TFEB KD attenuated 2-DG-directed autophagy, suggesting a mechanism whereby TFEB protects CSCs against 2-DG-induced stress. Our data indicate that TFEB modulates CSC metabolic stress response via autophagy and UPR. These findings reveal the novel role of TFEB in regulating CSCs during metabolic stress in triple-negative breast cancer.

DOI: https://doi.org/10.26508/lsa.202302259

Biochim Biophys Acta Mol Basis Dis. 2025 Jan 11. pii: S0925-4439(25)00013-4. [Epub ahead of print]1871(3): 167668

TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux.

Mengxue Zhao, Ruocheng Zhang, Xiuzhu Chen, Peixuan Li, Hui Yang, Bin Gao, Baoxin Li, Weina Zhou, Yuanyuan Wang, Yunliang Zhang, Li Zhong, Rui Guo.

Excessive alcohol consumption is a major cause of alcoholic cardiomyopathy (ACM) and myocardial injury. This study aims to investigate the role of transcription factor EB (TFEB) in ethanol-induced cardiac anomalies using a murine model, AC16 human cardiomyocytes, and human plasma. Wild-type mice treated with a TFEB activator (Compound 1) or vehicle (25 mg/kg/d) were challenged with or without ethanol (3 g/kg/d, i.p.) for three consecutive days. Cardiac geometry and function were evaluated by echocardiography. The expressions of TFEB, molecules related to mitochondria, markers of apoptosis, mitophagy and lysosomes were examined in heart tissues and AC16 cardiomyocytes. Mitochondrial function, lysosome activity, and their localizations were measured in AC16 cardiomyocytes. Levels of TFEB and autophagic markers were also detected in human serum from healthy individuals and patients with ACM. Ethanol administration in mice induced severe cardiac dysfunction accompanied by upregulated P62 and LC3B, downregulated TFEB, lysosomal markers and mitophagy-associated receptors in heart tissues. Ethanol toxicity also led to reduced mitochondrial and lysosomal activity. Interestingly, TFEB activation mitigated the detrimental effects caused by ethanol. Inhibition of autophagy abolished the anti-apoptotic effect of TFEB in AC16 cells. In conclusion, TFEB is beneficial in ethanol-induced cardiac anomalies by reducing apoptosis, recovering lysosomal activity, and restoring proper mitophagy and autophagic flux.

Keywords: Alcoholic cardiomyopathy; Apoptosis; Autophagic flux; Ethanol toxicity; Mitophagy; TFEB

DOI: https://doi.org/10.1016/j.bbadis.2025.167668