bims-raghud 2026-06-07 papers

Issue of 2026–06–07
three papers selected by
Irene Sambri, TIGEM

Biochem Biophys Res Commun. 2026 Jun 01. pii: S0006-291X(26)00841-7. [Epub ahead of print]827 154077

High-content screening identifies mTORC1-independent TFEB activators that promote protective autophagy.

Takashi Miyano, Kanzo Suzuki, Toshihiro Sera.

Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosome pathway. It becomes active upon nuclear translocation and induces the expression of genes involved in autophagy and lysosomal function. Mechanistic target of rapamycin complex 1 (mTORC1) inhibition typically triggers this process; however, chronic mTORC1 suppression often induces adverse metabolic and proliferative effects, necessitating the identification of mTORC1-independent mechanisms driving TFEB nuclear translocation. Therefore, this study aimed to identify pharmacological activators of TFEB nuclear translocation that function independently of mTORC1 inhibition. In this study, we developed a high-content screening assay to quantify TFEB nuclear translocation in HeLa cells and screened a library of 560 approved compounds. We identified two compounds, NSC-319726 and ML-SA1, that promoted TFEB nuclear translocation without reducing p70S6K phosphorylation, supporting an mTORC1-independent mechanism. Both compounds significantly increased LC3-II accumulation and the signal intensity of an autolysosomal marker, indicating enhanced autophagic flux. Functionally, these compounds protected the cells against staurosporine-induced apoptosis and hydrogen peroxide-induced oxidative stress. Notably, pre-treatment conferred significantly greater protection than co-treatment, suggesting that TFEB-mediated transcriptional remodeling is necessary for maximal cytoprotection. Overall, these findings highlight the potential of high-content phenotypic screening to identify mTORC1-independent TFEB activators and suggest NSC-319726 and ML-SA1 as pharmacological inducers of protective autophagy in vitro.

Keywords: Autophagy; Cellular stress; Screening; TFEB; mTORC1

DOI: https://doi.org/10.1016/j.bbrc.2026.154077

Cancer Rep (Hoboken). 2026 Jun;9(6): e70588

MITF Gain-of-Function Mutation in Metastatic Prostate Cancer: A Rare Finding With Potential Therapeutic Significance.

Paul J Pecorin, Nyembezi Dhliwayo, Matthew Demetrious, Ludimila Cavalcante, Veronica Rodriguez-Bravo, Josep Domingo Domenech, Thomas Westbrook.

BACKGROUND: Prostate cancer is the most common non-cutaneous malignancy in men and remains a leading cause of cancer-related mortality, particularly in aggressive variants. These tumors are usually associated with alterations in TP53, RB1, and PTEN. The microphthalmia-associated transcription factor (MITF) has been implicated in several malignancies, but its role in prostate cancer is less defined.
CASE: We report the first case of metastatic prostate adenocarcinoma harboring a gain-of-function MITF E318K mutation. The patient presented with high tumor burden, rapid progression, and evidence of tumor heterogeneity. The E318K mutation, previously linked to melanoma and renal cell carcinoma, enhances MITF transcriptional activity and may contribute to aggressive disease behavior.
CONCLUSION: This case expands current understanding of MITF in prostate cancer and raises important questions regarding its prognostic and therapeutic significance.

DOI: https://doi.org/10.1002/cnr2.70588

Exp Mol Med. 2026 Jun 02.

4E-BP1 acts as a molecular rheostat balancing regenerative healing and fibrotic scarring.

Hanyu Dou, Jianzhou Li, Lin Lin, Mengyu Jin, Jingyuan Wang, Hequn Fu, Jiongming Lu, Qinyi Chen, Leihong Xiang, Juan Wang, Xiaolei Ding.

Efficient wound healing relies on tightly coordinated protein synthesis to support the complex cellular activities underlying tissue repair. However, the mechanisms governing translational control during tissue regeneration remain incompletely defined. Here, we identify the mTORC1 effector 4E-binding protein 1 (4E-BP1) as a critical regulator of wound repair and fibrotic remodeling. Phosphorylated 4E-BP1 was markedly increased in wounds and fibrotic tissues, indicating dynamic engagement of the mTORC1/4E-BP1 signaling axis during repair. Functional studies revealed that genetic ablation of 4E-BP1, mimicking fully phosphorylated 4E-BP1, enhanced re-epithelialization, angiogenesis, and granulation tissue formation in wound tissues, yet concurrently promoted myofibroblast activation and excessive collagen deposition, and fibrotic progression in bleomycin-induced skin fibrosis. Conversely, sustained overexpression of 4E-BP1 impaired wound closure and attenuated fibrotic responses. Moreover, in vitro, 4E-BP1 expression directly governed transforming growth factor-β1-mediated fibroblast collagen synthesis. Phosphorylated 4E-BP1 levels and related transcriptional signatures were elevated in human skin fibrotic scar tissues. These findings demonstrate that 4E-BP1 acts as an mTORC1-downstream effector that shapes the balance between reparative efficiency and fibrotic remodeling. Targeting the mTORC1/4E-BP1 signaling axis may therefore offer novel therapeutic opportunities to optimize wound healing and prevent pathological scarring.

DOI: https://doi.org/10.1038/s12276-026-01724-0