bims-raghud 2026-03-29 papers

Issue of 2026–03–29
four papers selected by
Irene Sambri, TIGEM

Acta Pharmacol Sin. 2026 Mar 24.

MCOLN1-mediated PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia.

Shi-Qi Liu, Yue-Yang Liu, Xiao-Xiao Fu, Pei-Rui Cui, Xin Wang, Sai-Qian Wang, Chun-Fu Wu, Li-Hui Wang, Jing Luo, Jing-Yu Yang.

We previously reported that transcription factor EB (TFEB) plays a crucial role in regulating the ischemic stroke (IS)-mediated dynamic changes of autophagic flux. Protein phosphatase 3 (PPP3) may regulate the transcriptional activity of TFEB. However, the main isoform of the PPP3 catalytic subunit (PPP3C) involved in TFEB activation, the PPP3-binding site in TFEB, and the upstream regulatory mechanism of PPP3 activation after cerebral ischemia are still unknown. Here, we show that the interaction between TFEB and PPP3 catalytic subunit B (PPP3CB), but not PPP3CA, is strengthened after IS. Knockdown of PPP3CB, but not PPP3CA, significantly inhibited the oxygen glucose deprivation (OGD)-induced increase in the transcriptional activity of TFEB, blocked autophagic flux, and exacerbated neuronal death. Furthermore, the YLAVP peptide, which blocks the LxVP motif-binding site of PPP3C, repressed TFEB transcriptional activity and autophagic flux, and exacerbated neuronal death after OGD. Treatment with ML-SI1, which inhibits the lysosomal calcium channel MCOLN1, blocked the OGD-induced enhancement of TFEB transcriptional activity and autophagic flux, and further aggravated neuronal death. These effects were partly reversed by the MCOLN1 agonist ML-SA1. The PPP3 inhibitor cyclosporin A (CsA) abolished the ML-SA1-induced TFEB transcriptional activation and reduced neuronal death. Our findings identify for the first time that MCOLN1-mediated-PPP3CB activation alleviates neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia. The LxVP motif is required for the interaction between PPP3 and TFEB in response to OGD. This study provides an in-depth insight into the mechanisms underlying TFEB-mediated activation of autophagic flux following IS. Schematic diagram showing how MCOLN1-mediated activation of PPP3CB reduces neuronal damage by promoting TFEB-dependent autophagic flux in permanent cerebral ischemia.

Keywords: LxVP motif-binding site; MCOLN1; autophagy-lysosomal pathway; protein phosphatase 3 catalytic subunit B; transcription factor EB

DOI: https://doi.org/10.1038/s41401-026-01762-4

Mol Oncol. 2026 Mar 26.

Hippo pathway at the crossroads of stemness and therapeutic resistance in breast cancer.

Giulia Schiavoni, Antonella Palmese, Stefano Scalera, Laura Cipriani, Davide Mascolo, Patrizia Vici, Teresa Arcuri, Lorena Filomeno, Eriseld Krasniqi, Giovanni Blandino, Giulia Bon, Marcello Maugeri-Saccà.

Breast cancer, the most frequently diagnosed cancer in women globally, is a heterogeneous disease with distinct subtypes requiring distinct therapeutic approaches. Regardless of molecular subtyping, breast cancer stem cells significantly contribute to tumor heterogeneity, distant dissemination, and therapeutic resistance. The Hippo pathway is a key regulator of organogenesis and tissue development, and its deregulation is common in breast cancer and linked to cancer stem cell features across several cancer types. Dysfunctional pathway activity leads to the aberrant activation of Hippo downstream effectors, the Yes-associated protein (YAP) and its paralog transcriptional co-activator with PDZ-binding motif (TAZ), which promote epithelial-to-mesenchymal transition, growth factor-independent proliferation, and maintenance of the breast cancer stem cells' niche. This review summarizes the regulation of the Hippo pathway, emphasizing its significant role in coordinating stemness-related mechanisms in breast cancer. An overview of how the Hippo pathway fuels stemness in triple-negative breast cancer, the most aggressive BC subtype, is then provided. We also discuss how the activation of stem cell-like properties, driven by dysregulation of the Hippo pathway, contributes to the development of resistance to current therapies across the spectrum of breast cancer subtypes.

Keywords: Hippo pathway; breast cancer; cancer therapy resistance; stemness; triple‐negative breast cancer

DOI: https://doi.org/10.1002/1878-0261.70232

Cancers (Basel). 2026 Mar 16. pii: 958. [Epub ahead of print]18(6):

TFE3-Rearranged and TFEB-Altered Renal Cell Carcinomas: Molecular Landscape and Therapeutic Advances.

Mikel Portu, Mario Balsa, Maria Cotaina, Georgia Anguera, Xavier García Del Muro, Ferran Algaba, Pablo Maroto.

Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of TFEB-amplified RCC remains uncertain.

Keywords: MiT-RCC; TFE3; TFEB; gene fusion; immune checkpoint inhibitor; precision oncology; translocation renal cell carcinoma; tyrosine kinase inhibitor

DOI: https://doi.org/10.3390/cancers18060958

J Neuropathol Exp Neurol. 2026 Mar 22. pii: nlag010. [Epub ahead of print]

RagC and Map4K3 deficiency in high-grade gliomas drives proliferation and modulates mTORC1-dependent cellular functions.

Julian Kahr, Roberto Diaz-Peregrino, Ibrahim E Sandalcioglu, Peter John, Christian Mawrin.

Cellular growth and homeostasis via amino acid-responsive pathways are mediated by the mTOR signaling pathway. Rag GTPases and Map4K3 modify mTOR signaling as amino acid sensors. Altered mTOR signaling in relation to amino acid sensors might represent factors that modify proliferation and treatment responses in astrocytic tumors. To investigate this hypothesis, RagC and Map4K3 expression was studied in human gliomas, glioma cells (U87MG/U138MG), and nonglial cells (MCF-7, IOMM-Lee). RagC and Map4K3 knockout in glioma cells was generated using CRISPR-Cas and shRNA. High-grade astrocytomas had significantly reduced immunoreactivity for RagC and Map4K3 compared to low-grade astrocytomas. RagC- and Map4K3-deficient glioma cells had significantly increased proliferation and showed altered morphology and motility. Induced amino acid deficiency (leucine deprivation) reduced proliferation in Map4K3- but not in RagC-deficient cells. mTOR signaling in RagC- and Map4K3-deficient U87 cells was altered with increased phosphorylation of p70S6K and increased expression of RagD and transcription factor EB. In this context, uncoupled, exaggerated autophagy occurred in Map4K3-deficient U87 cells. In contrast, RagC-deficient U87 cells showed increased senescence but no autophagy induction. These data show that losses of RagC and Map4K3 in malignant gliomas have proliferation-inducing effects and differentially modulate key mTOR signaling-dependent cellular mechanisms.

Keywords: Map4K3; RagC; amino acid sensor; autophagy; glioma

DOI: https://doi.org/10.1093/jnen/nlag010