bims-raghud 2026-02-01 papers

Issue of 2026–02–01
five papers selected by
Irene Sambri, TIGEM

Int J Mol Sci. 2026 Jan 16. pii: 905. [Epub ahead of print]27(2):

Identification of KHS-101 as a Transcription Factor EB Activator to Promote α-Synuclein Degradation.

Haizhen Zhu, Anqi Ren, Ting Li, Tao Zhou, Ailing Li, Xin Pan, Liang Chen, Jiayi Chen.

Neurodegenerative disorders are increasingly linked to a progressive decline in lysosomal function. Activating Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, has therefore emerged as a promising therapeutic strategy to enhance cellular clearance in these conditions. In this study, we identified KHS-101 as a novel TFEB activator through a high-throughput screen of blood-brain-barrier-permeable small molecules. We demonstrated that KHS-101 promotes TFEB nuclear translocation, enhances lysosomal biogenesis and proteolytic activity, and increases autophagic flux. Furthermore, KHS-101 significantly accelerates the degradation of pathogenic A53T mutant α-synuclein in a cellular model of Parkinson's disease, suggesting its potential to mitigate α-synuclein-mediated proteotoxicity and hold neuroprotective potential. Our findings identify KHS-101 as a potent TFEB activator and highlight the therapeutic potential of modulating the autophagy-lysosomal pathway for treating Parkinson's disease and related disorders.

Keywords: KHS-101; Parkinson’s disease; TFEB; autophagy–lysosome pathway; lysosome degradation; α-synuclein

DOI: https://doi.org/10.3390/ijms27020905

Oxf Med Case Reports. 2026 Jan;2026(1): omaf187

A rare early-onset bilateral renal cysts, focal seizures in a 1-year-old male with tuberous sclerosis and No mutation identified.

Dana Salahat, Ramzi Mujahed, Mohanad Jaber, Mohammed Tahayneh, Nisreen Khalifa, Qais Alnjoom, Rani Sabra, Motasem Doudin, Raef Sabra, Ibraheem AbuAlrub.

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder characterized by the development of benign tumors in multiple organs. This report presents an unusual case of early-onset renal cystic disease in a 1-year-old male with TSC, despite the absence of detectable mutations in the TSC1 or TSC2 genes. Postnatal imaging revealed bilateral polycystic kidney disease by 2 months of age. The patient presented with secondary hypertension and seizures. Neuroimaging confirmed cortical tubers and a subependymal giant cell astrocytoma (SEGA), while echocardiography identified cardiac rhabdomyomas. Despite these clinical findings, genetic testing failed to detect mutations in the TSC1 or TSC2 genes. This case highlights the importance of considering TSC as a potential diagnosis in cases of early-onset renal cystic disease, even in the absence of detectable TSC gene mutations. Additionally, the case emphasizes the risk of severe renal involvement in TSC, necessitating early recognition and management.

Keywords: case report; polycystic kidney; subependymal giant cell astrocytoma; tuberous sclerosis complex

DOI: https://doi.org/10.1093/omcr/omaf187

Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00031-6. [Epub ahead of print]

Lysosomes as hubs of metabolic sensing and cellular homeostasis.

Aakriti Jain, Roberto Zoncu.

Lysosomes are hubs that couple macromolecular breakdown to cell-wide signaling by sensing metabolic, damage-associated, and environmental cues. Nutrients liberated in the lysosomal lumen as end-products of macromolecular degradation, including amino acids, lipids, and iron, are exported by dedicated transporters for utilization in the cytoplasm. Nutrient transport across the lysosomal membrane is coupled to its sensing by specialized signaling complexes on the cytoplasmic face, which, in response, mediate communication with other organelles and control cell-wide programs for growth, catabolism, and stress response. Lysosomes acquire specialized sensing-signaling features in immune cells, where they shape antigen processing, innate immune signaling, and inflammatory cell death, and in neurons, where they act as sentinels of proteostatic and mitochondrial stress, supporting local translation, organelle quality control, and neuroimmune crosstalk. We highlight recently identified pathways and players that position lysosomes as integrators of nutrient status and organelle health to drive tissue-specific physiology.

Keywords: amyloid; autophagy; inflammation; lysosome; mTORC1; metabolites; neurodegeneration; organelle contacts; signaling

DOI: https://doi.org/10.1016/j.molcel.2026.01.011

Int J Mol Sci. 2026 Jan 16. pii: 918. [Epub ahead of print]27(2):

Lipid Droplets in Cancer: New Insights and Therapeutic Potential.

Shriya Joshi, Chakravarthy Garlapati, Amartya Pradhan, Komal Gandhi, Adepeju Balogun, Ritu Aneja.

The progression of neoplastic diseases is driven by a complex interplay of biological processes, including uncontrolled proliferation, enhanced invasion, metastasis, and profound metabolic reprogramming. Among the hallmarks of cancer, as revised by Hanahan and Weinberg, the reprogramming of energy metabolism has emerged as a critical feature that enables cancer cells to meet their heightened bioenergetic and biosynthetic demands. One significant aspect of this metabolic adaptation is the accumulation of lipid droplets (LDs) dynamic, cytoplasmic organelles primarily involved in lipid storage and metabolic regulation. LDs serve as reservoirs of neutral lipids and play a multifaceted role in cancer cell physiology. Their accumulation is increasingly recognized as a marker of tumor aggressiveness and poor prognosis. By storing lipids, LDs provide a readily accessible source of energy and essential building blocks for membrane synthesis, supporting rapid cell division and growth. Moreover, LDs contribute to cellular homeostasis by modulating oxidative stress, maintaining redox balance, and regulating autophagy, particularly under nutrient-deprived or hypoxic conditions commonly found in the tumor microenvironment. Importantly, LDs have been implicated in the development of resistance to cancer therapies. They protect cancer cells from the cytotoxic effects of chemotherapeutic agents by buffering endoplasmic reticulum (ER) stress, inhibiting apoptosis, and facilitating survival pathways. The presence of LDs has been shown to correlate with increased resistance to a variety of chemotherapeutic drugs, although the precise molecular mechanisms underlying this phenomenon remain incompletely understood. Emerging evidence suggests that chemotherapy itself can induce changes in LD accumulation, further complicating treatment outcomes. Given their central role in cancer metabolism and therapy resistance, LDs represent a promising target for therapeutic intervention. Strategies aimed at disrupting lipid metabolism or inhibiting LD biogenesis have shown potential in sensitizing cancer cells to chemotherapy and overcoming drug resistance. In this review, we comprehensively examine the current understanding of LD biology in cancer, highlight studies that elucidate the link between LDs and drug resistance, and discuss emerging approaches to target lipid metabolic pathways to enhance therapeutic efficacy across diverse cancer types.

Keywords: cancer metabolism; drug resistance; lipid droplets (LDs); metabolic reprogramming; therapeutic targeting

DOI: https://doi.org/10.3390/ijms27020918

Mol Cancer. 2026 Jan 27.

Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.

Hongling Zhong, Renjie Pan, Yuzhen Ouyang, Tengfei Xiao, Wangning Gu, Hongmin Yang, Hui Wang, Hucheng Li, Tianfang Peng, Pan Chen.

Mitochondria are central to health and disease by precisely regulating metabolism and interacting closely with other organelles. Mitochondrial dysfunction contributes to the initiation and development of numerous diseases, including cancer. In cancer cells, metabolic reprogramming, impaired mitochondrial quality control, and mitochondrial DNA damage are linked to tumor initiation, development, and metastasis. Dysregulated mitochondrial function in cells within the tumor microenvironment, such as CD8 + T cells, also promotes cancer progression. Therapeutic approaches targeting mitochondria range from dietary interventions to small-molecule drugs aimed at restoring mitochondrial dysfunction. In this review, we summarize the relationships between mitochondrial dysfunction and cancer from the perspectives of metabolism, quality control, mitochondrial DNA stability, ion homeostasis, and the tumor microenvironment. We also provide updates on mitochondria-targeted therapies, highlighting key translational gaps from bench to bedside. Finally, we discuss future directions for mitochondria-targeted cancer therapy, emphasizing mitochondrial homeostasis as a critical target for improving therapeutic outcomes.

Keywords: Cancer Metabolism Reprograming; Mitochondrial DNA (mtDNA) Damage; Mitochondrial Homeostasis; Mitochondrial-Targeted Therapies; Tumor Microenvironment

DOI: https://doi.org/10.1186/s12943-026-02571-3