bims-raghud 2025-06-01 papers

Issue of 2025–06–01
six papers selected by
Irene Sambri, TIGEM

Life Sci. 2025 May 24. pii: S0024-3205(25)00396-0. [Epub ahead of print] 123761

Autophagy in cardiac pathophysiology: Navigating the complex roles and therapeutic potential in cardiac fibrosis.

Cardiac fibrosis is a critical factor in cardiac structural remodeling and dysfunction, closely associated with the progression of various cardiovascular diseases (CVDs), including heart failure and myocardial infarction (MI). It is characterized by excessive extracellular matrix (ECM) deposition, which disrupts normal cardiac architecture and impairs cardiac function. Autophagy, a cellular degradation and recycling mechanism, is essential for maintaining cardiac homeostasis, mitigating stress responses, and preventing cellular damage. Recent studies have revealed a significant link between autophagy and cardiac fibrosis, suggesting that autophagic dysregulation can exacerbate fibrosis by promoting fibroblast activation and ECM accumulation. Conversely, proper autophagic activity may attenuate cardiac fibrosis by removing damaged cellular components and regulating fibrotic signaling pathways. This review examines the role of autophagy in cardiac fibrosis. It also emphasizes potential pharmacological strategies that can be used to modulate autophagic processes. These strategies may serve as therapeutic approaches for treating cardiac fibrosis, with the ultimate goal of preventing excessive fibrosis and enhancing cardiac function.

Keywords: Autophagy; Cardiac fibrosis; Cardiac pathophysiology; Heart failure

DOI: https://doi.org/10.1016/j.lfs.2025.123761

Physiol Rep. 2025 May;13(10): e70383

Regulation of TFEB in human placental Cytotrophoblasts and Syncytiotrophoblasts.

A Mathew, J S Trausch-Azar, C Azar, M Schuetz, M R Mahjoub, A L Schwartz.

While cellular proteins exist in a dynamic state maintained by the balance of synthesis and degradation, there is a paucity of information on these processes in placental trophoblasts, including within cytotrophoblasts which differentiate into multi-nucleate syncytiotrophoblasts. TFEB, a transcription factor with a myriad of cellular activities, is one of the most abundant genes expressed in syncytiotrophoblasts compared to cytotrophoblasts. TFEB is localized to the nucleus of human BeWo differentiated syncytiotrophoblasts and to the cytoplasm of the undifferentiated cytotrophoblasts. Within both the cytotrophoblasts and syncytiotrophoblasts, TFEB exists in subcellular compartments as both phosphorylated and unphosphorylated forms and translocates between cytoplasm and nucleus upon amino acid starvation/refeeding. Endogenous TFEB and endogenous phospho-TFEB are both rapidly (t1/2 ~ 2-3 h) degraded via the ubiquitin proteasome system in cytotrophoblasts and in syncytiotrophoblasts. These results suggest dynamic regulatory processes during trophoblast development/differentiation.

Keywords: cytotrophoblast; degradation; placental; syncytiotrophoblast; ubiquitin

DOI: https://doi.org/10.14814/phy2.70383

Orphanet J Rare Dis. 2025 May 27. 20(1): 256

mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node.

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

Keywords: AKT; Birt-Hogg-Dubé; Everolimus; PI3K; PTEN; Peutz-Jeghers; Rapamycin; Rare diseases; Tuberous sclerosis complex; mTOR

DOI: https://doi.org/10.1186/s13023-025-03740-1

J Transl Med. 2025 May 25. 23(1): 583

The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance.

Haiqing Jia, Jing Wei, Wei Zheng, Zhuo Li.

Cancer stem cells (CSCs) constitute a small yet crucial subgroup in tumors, known for their capacity to self-renew, differentiate, and promote tumor growth, metastasis, and resistance to therapy. These characteristics position CSCs as significant factors in tumor recurrence and unfavorable clinical results, emphasizing their role as targets for therapy. Autophagy, an evolutionarily preserved cellular mechanism for degradation and recycling, has a complex function in cancer by aiding cell survival during stress and preserving balance by eliminating damaged organelles and proteins. Although autophagy can hinder tumor growth by reducing genomic instability, it also aids tumor advancement, particularly in harsh microenvironments, highlighting its dual characteristics. Recent research has highlighted the complex interactions between autophagy and CSCs, showing that autophagy governs CSC maintenance, boosts survival, and aids in resistance to chemotherapy and radiotherapy. On the other hand, in specific situations, autophagy may restrict CSC growth by increasing differentiation or inducing cell death. These intricate interactions offer both obstacles and possibilities for therapeutic intervention. Pharmacological modulation of autophagy, via inhibitors like chloroquine or by enhancing autophagy when advantageous, has demonstrated potential in making CSCs more responsive to standard treatments. Nonetheless, applying these strategies in clinical settings necessitates a better understanding of context-dependent autophagy dynamics and the discovery of dependable biomarkers indicating autophagic activity in CSCs. Progressing in this area might unveil novel, accurate strategies to tackle therapy resistance, lessen tumor recurrence, and ultimately enhance patient outcomes.

Keywords: Apoptosis; Autophagy; Cancer stem cells; Cell death; Drug resistance

DOI: https://doi.org/10.1186/s12967-025-06595-z

Cureus. 2025 Apr;17(4): e83143

Chromophobe Renal Cell Carcinoma With Sarcomatoid Differentiation: A Case Report and Review of the Literature.

Mouhsine Omari, Mohammed Bendimya, Fadoua Jebrouni, Nassira Karich, Ouissam Al Jarroudi, Sami Aziz Brahmi, Amal Bennani, Said Afqir.

Chromophobe renal cell carcinoma is a rare entity with an excellent prognosis compared with clear renal cell carcinoma and is characterized by distinct molecular and genetic specificity. The presence of a sarcomatoid component is an uncommon phenomenon, which indicates a high risk of metastasis and a poor prognosis. We present the case of a 44-year-old patient with chromophobe renal cell carcinoma with a sarcomatoid component. Therapeutic management presents a significant challenge given the absence of standards of care for this rare entity. The current treatments are based on vascular endothelial growth factor tyrosine kinase inhibitors, mammalian target of rapamycin pathway inhibitors, and immune checkpoint inhibitors. Close monitoring based on clinical, biological, and radiological examinations is necessary for rapid and appropriate interventions. Moreover, this histological variant represents a major clinical challenge, not only because of its aggressive behavior but also due to the absence of specific clinical manifestations and its frequent incidental discovery at an advanced stage, further complicating early diagnosis and management.

Keywords: chromophobe carcinoma; immune checkpoint inhibitors; prognosis; sarcomatoid differentiation; target therapy

DOI: https://doi.org/10.7759/cureus.83143

Int J Mol Sci. 2025 May 16. pii: 4780. [Epub ahead of print]26(10):

SGLT2 Inhibitors in Cancer Patients: A Comprehensive Review of Clinical, Biochemical, and Therapeutic Implications in Cardio-Oncology.

Alessandra Greco, Maria Laura Canale, Vincenzo Quagliariello, Stefano Oliva, Andrea Tedeschi, Alessandro Inno, Marzia De Biasio, Irma Bisceglia, Luigi Tarantini, Nicola Maurea, Alessandro Navazio, Marco Corda, Attilio Iacovoni, Furio Colivicchi, Massimo Grimaldi, Fabrizio Oliva.

Patients with active cancer and cancer survivors are at a markedly increased risk for developing cardiovascular comorbidities, including heart failure, coronary artery disease, and renal dysfunction, which are often compounded by the cardiotoxic effects of cancer therapies. This heightened cardiovascular vulnerability underscores the urgent need for effective, safe, and evidence-based cardioprotective strategies to reduce both cardiovascular morbidity and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2is), a class of drugs originally developed for the treatment of type 2 diabetes, have demonstrated significant cardiovascular and renal benefits in high-risk populations, independent of glycemic control. Among the currently available SGLT2i, such as empagliflozin, canagliflozin, dapagliflozin, and sotagliflozin, there is growing evidence supporting their role in reducing major adverse cardiovascular events (MACEs), hospitalization for heart failure, and the progression of chronic kidney disease. Recent preclinical and clinical data suggest that SGLT2is exert cardioprotective effects through multiple mechanisms, including the modulation of inflammasome activity, specifically by reducing NLRP3 inflammasome activation and MyD88-dependent signaling, which are critical drivers of cardiac inflammation and fibrosis. Moreover, SGLT2is have been shown to enhance mitochondrial viability in cardiac cells, promoting improved cellular energy metabolism and function, thus mitigating cardiotoxicity. This narrative review critically evaluates the emerging evidence on the cardiorenal protective mechanisms of SGLT2is, with a particular focus on their potential role in cardio-oncology. We explore the common pathophysiological pathways between cardiovascular dysfunction and cancer, the molecular rationale for the use of SGLT2is in cancer patients, and the potential benefits in both primary and secondary prevention of cardiovascular toxicity related to oncological treatments. The aim is to propose a therapeutic paradigm utilizing SGLT2is to reduce cardiovascular mortality, MACE, and the burden of cardiotoxicity in high-risk oncology patients, fostering an integrated approach to cardio-oncology care.

Keywords: SGLT2; cancer; cardioprotection; cardiotoxicity; inflammation; metabolism; pathology

DOI: https://doi.org/10.3390/ijms26104780