bims-raghud 2025-04-06 papers

Issue of 2025–04–06
six papers selected by
Irene Sambri, TIGEM

Elife. 2025 Apr 04. pii: RP103137. [Epub ahead of print]13

Small-molecule activation of TFEB alleviates Niemann-Pick disease type C via promoting lysosomal exocytosis and biogenesis.

Kaili Du, Hongyu Chen, Zhaonan Pan, Mengli Zhao, Shixue Cheng, Yu Luo, Wenhe Zhang, Dan Li.

Niemann-Pick disease type C (NPC) is a devastating lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Currently, there is no treatment for NPC. Transcription factor EB (TFEB), a member of the microphthalmia transcription factors (MiTF), has emerged as a master regulator of lysosomal function and promoted the clearance of substrates stored in cells. However, it is not known whether TFEB plays a role in cholesterol clearance in NPC disease. Here, we show that transgenic overexpression of TFEB, but not TFE3 (another member of MiTF family) facilitates cholesterol clearance in various NPC1 cell models. Pharmacological activation of TFEB by sulforaphane (SFN), a previously identified natural small-molecule TFEB agonist by us, can dramatically ameliorate cholesterol accumulation in human and mouse NPC1 cell models. In NPC1 cells, SFN induces TFEB nuclear translocation via a ROS-Ca2+-calcineurin-dependent but MTOR-independent pathway and upregulates the expression of TFEB-downstream genes, promoting lysosomal exocytosis and biogenesis. While genetic inhibition of TFEB abolishes the cholesterol clearance and exocytosis effect by SFN. In the NPC1 mouse model, SFN dephosphorylates/activates TFEB in the brain and exhibits potent efficacy of rescuing the loss of Purkinje cells and body weight. Hence, pharmacological upregulating lysosome machinery via targeting TFEB represents a promising approach to treat NPC and related lysosomal storage diseases, and provides the possibility of TFEB agonists, that is, SFN as potential NPC therapeutic candidates.

Keywords: NPC1; TFEB agonists; cell biology; cholesterol accumulation; human; lysosome; mouse

DOI: https://doi.org/10.7554/eLife.103137

J Am Soc Nephrol. 2025 04 01. 36(4): 587-601

TRPML-1 Dysfunction and Renal Tubulopathy in Mucolipidosis Type IV.

Background: Loss-of-function mutations in the lysosomal channel transient receptor potential cation channel (TRPML-1) cause mucolipidosis type IV (MLIV), a rare lysosomal storage disease characterized by neurological defects, progressive vision loss, and achlorhydria. Recent reports have highlighted kidney disease and kidney failure in patients with MLIV during the second to third decade of life; however, the molecular mechanisms driving kidney dysfunction remain poorly understood.
Methods: A cross-sectional review of medical records from 21 patients with MLIV (ages 3–43 years) was conducted to assess kidney function impairment. In addition, we examined the kidney phenotype of MLIV mice at various ages, along with human kidney cells silenced for TRPML-1 and primary tubular cells from wild-type and MLIV mice. Immunohistology and cell biology approaches were used to phenotype nephron structure, the endolysosomal compartment, and inflammation. Kidney function was assessed through proteomic analysis of mouse urine and in vivo kidney filtration measurements.
Results: Of the 21 patients with MLIV, only adults were diagnosed with stage 2–3 CKD. Laboratory abnormalities included lower eGFR and higher levels BUN/creatine in blood and proteinuria. In MLIV mice, we observed significant alterations in endolysosomal morphology, function, and impaired autophagy in proximal and distal tubules. This led to the accumulation of megalin (LRP2) in the subapical region of proximal tubular cells, indicating a block in apical receptor–mediated endocytosis. In vivo and in vitro experiments confirmed reduced fluid-phase endocytosis and impaired uptake of ligands, including β-lactoglobulin, transferrin, and albumin in MLIV proximal tubular cells. Urine analysis revealed tubular proteinuria and enzymuria in mice with MLIV. In addition, early-stage disease was marked by increased inflammatory markers, fibrosis, and activation of the proinflammatory transcription factor NF-κB, coinciding with endolysosomal defects. Importantly, adeno-associated viral–mediated TRPML-1 gene delivery reversed key pathological phenotypes in MLIV mice, underscoring TRPML-1's critical role in kidney function.
Conclusions: Our findings link TRPML-1 dysfunction to the development of kidney disease in MLIV.

DOI: https://doi.org/10.1681/ASN.0000000567

BMC Nephrol. 2025 Apr 01. 26(1): 166

The prospect of novel orphan therapeutic protocol for TSC2/PKD1 contiguous gene syndrome: a case report.

Bogdan D Agavriloaei, Radu C Costache, Ramona G Babici, Stela Racoviță, Gianina Dodi, Adrian C Covic, Irina L Mititiuc.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD, OMIM # 601313, # 173900) and tuberous sclerosis complex (TSC2, OMIM # 191092, #613254) are inherited multisystemic diseases that rarely associate. Large deletion on chromosome 16 can result in TSC2/PKD1 contiguous gene (deletion) syndrome (PKDTS, OMIM # 600273) presenting significant diagnostic and management challenges.
CASE PRESENTATION: A 50-year-old male presented clinical features consistent with autosomal dominant polycystic kidney disease (ADPKD) and signs of tuberous sclerosis complex (TSC), such as multiple facial angiofibroma, cortical tubers, cerebral hamartomas, and renal and hepatic angiomyolipomas, was investigated for the multisystemic disease pattern. Genetic testing confirmed the diagnosis of TSC2/PKD1 contiguous gene deletion syndrome (PKDTS), leading to the initiation of tolvaptan treatment to reduce the progression of ADPKD and considering everolimus as a potential therapeutic solution to decrease the size of angiomyolipomas, thereby minimizing the risk of spontaneous bleeding. Our report underlines for the first time, up to our knowledge, that the proposed therapy protocol for PKD1/TSC2 contiguous gene deletion syndrome could have potential.
CONCLUSIONS: This case illustrates the importance of recognizing overlapping genetic disorders, and providing insights into an innovative therapeutic approach. By integrating detailed clinical assessment with genetic testing, the diagnosis was clarified, and targeted therapies can be selected to address the dual impact of ADPKD and TSC; however, further studies are needed to evaluate the efficacy and safety of this approach. We also emphasize the need to recognize other cases of renal polycystic disease associated with angiomyolipomas and cutaneous manifestations.

Keywords: TSC2/PKD1 contiguous gene deletion syndrome (PKDTS); Angiomyolipomas (AML); Autosomal dominant polycystic kidney disease (ADPKD); Case report; Everolimus therapy; Genetic testing; Tolvaptan therapy; Tuberous sclerosis complex (TSC)

DOI: https://doi.org/10.1186/s12882-025-04088-1

Mol Cancer. 2025 Apr 02. 24(1): 107

Wnt signaling in cancer: from biomarkers to targeted therapies and clinical translation.

Muhammad Tufail, Can-Hua Jiang, Ning Li.

The Wnt signaling pathway plays a crucial role in development and tissue homeostasis, regulating key cellular processes such as proliferation, differentiation, and apoptosis. However, its abnormal activation is strongly associated with tumorigenesis, metastasis, and resistance to therapy, making it a vital target for cancer treatment. This review provides a comprehensive insight into the role of Wnt signaling in cancer, examining its normal physiological functions, dysregulation in malignancies, and therapeutic potential. We emphasize the importance of predicting Wnt signaling sensitivity and identify key biomarkers across various cancer types. Additionally, we address the challenges and future prospects of Wnt-targeted therapies, including biomarker discovery, advancements in emerging technologies, and their application in clinical practice.

Keywords: Biomarkers; Cancer therapy; Challenges and Future directions; Wnt signaling pathway; ncRNAs

DOI: https://doi.org/10.1186/s12943-025-02306-w

Curr Mol Pharmacol. 2025 Apr 03.

Targeting of Lysosomes as a Therapeutic Target in Cancer.

Biyu Liu, Chengsheng Yang, Jiayi Liu, Minzhi Peng, Junquan Mao, Sanyuan Tang, Weiguo Huang.

Lysosomes are important intracellular organelles involved in degradation metabolism, maintenance of homeostasis, cell survival and programmed death regulation, and play an important role in immunity. Some studies have shown that lysosomes are closely linked to tumor development. Lysosomes in tumor cells increase in size and activity to adapt to rapid proliferation. Cancer cells provide strong support for their unrestricted growth and proliferation by precisely regulating the number, composition and functional activities of lysosomes and also create favorable conditions for malignant behaviors such as survival, migration, invasion, and metastatic spread of cancer cells. Lysosomes play a central role in tumor progression, and in recent years, lysosomes have become an important target for anticancer strategies aimed at interfering with their function or modulating related signaling pathways to inhibit tumors. Current anti-cancer strategies include the following five aspects: (1) targeting tumor cell energy metabolism and lysosomes to inhibit growth; (2) inhibiting lysosomal histone proteases to block degradation metabolism; (3) destabilizing lysosomal membranes to trigger tumor cell death; (4) modulating lysosomal calcium signaling to affect tumor cell function; and (5) interfering with the mTOR signaling pathway to inhibit tumor growth and proliferation. These lysosome-targeted anticancer strategies offer broad prospects and potential for the development of novel anticancer drugs and therapies and are expected to bring more effective and safer therapeutic options for cancer patients.

Keywords: Antitumor therapy; Autophagy.; Biological functions; Lysosome

DOI: https://doi.org/10.2174/0118761429354659250320051057

Signal Transduct Target Ther. 2025 Apr 04. 10(1): 106

Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances.

Chen Xue, Qingfei Chu, Qingmiao Shi, Yifan Zeng, Juan Lu, Lanjuan Li.

The Wnt signaling pathway is critically involved in orchestrating cellular functions such as proliferation, migration, survival, and cell fate determination during development. Given its pivotal role in cellular communication, aberrant Wnt signaling has been extensively linked to the pathogenesis of various diseases. This review offers an in-depth analysis of the Wnt pathway, detailing its signal transduction mechanisms and principal components. Furthermore, the complex network of interactions between Wnt cascades and other key signaling pathways, such as Notch, Hedgehog, TGF-β, FGF, and NF-κB, is explored. Genetic mutations affecting the Wnt pathway play a pivotal role in disease progression, with particular emphasis on Wnt signaling's involvement in cancer stem cell biology and the tumor microenvironment. Additionally, this review underscores the diverse mechanisms through which Wnt signaling contributes to diseases such as cardiovascular conditions, neurodegenerative disorders, metabolic syndromes, autoimmune diseases, and cancer. Finally, a comprehensive overview of the therapeutic progress targeting Wnt signaling was given, and the latest progress in disease treatment targeting key components of the Wnt signaling pathway was summarized in detail, including Wnt ligands/receptors, β-catenin destruction complexes, and β-catenin/TCF transcription complexes. The development of small molecule inhibitors, monoclonal antibodies, and combination therapy strategies was emphasized, while the current potential therapeutic challenges were summarized. This aims to enhance the current understanding of this key pathway.

DOI: https://doi.org/10.1038/s41392-025-02142-w