bims-lycede 2026-03-01 papers

Mol Biol Cell. 2026 Feb 25. mbcE24030109

Autophagosome turnover requires Arp2/3 complex-mediated maintenance of lysosomal integrity.

Corey J Theodore, Lianna H Wagner, Kenneth G Campellone.

Autophagy is an intracellular degradation process that maintains homeostasis, responds to stress, and plays key roles in preventing aging and disease. Autophagosome biogenesis, vesicle rocketing, and autolysosome tubulation are controlled by multiple actin cytoskeletal factors, but the impact of actin assembly on completion of the autophagic degradation pathway is not well understood. Here we studied autophagosomes and lysosomes in mouse fibroblasts harboring an inducible knockout (iKO) of the Arp2/3 complex, an essential actin nucleator. Arp2/3 complex ablation resulted in increased basal levels of autophagy receptors and lipidated membrane proteins from the LC3 and GABARAP families. Such phenotypes were accompanied by the steady-state presence of abnormally high numbers of autolysosomes and an inability of the Arp2/3 complex-deficient cells to complete autolysosome turnover due to lysosomal damage. When normal cells were treated with a lysosomal membrane-disrupting agent, the Arp2/3-activating protein WHAMM was recruited to lysosomes, and Arp2/3 complex activity was required for restoring intact lysosomal structure. Deletion of WHAMM in mouse or human fibroblasts decreased Arp2/3 localization to lysosomes and increased lysosomal damage. These results reveal the importance of the Arp2/3 complex and WHAMM for autophagic degradation and uncover a new role for the actin nucleation machinery in maintaining lysosomal integrity.

DOI: https://doi.org/10.1091/mbc.E24-03-0109

Biochem Pharmacol. 2026 Feb 25. pii: S0006-2952(26)00179-6. [Epub ahead of print] 117848

Celastrol induces liver cancer cell death via TFEB-Mediated lysosome activation and ROS-Dependent ferroptosis.

Jing Ma, Yong-Zhuo Li, Mei-Xiu Li, Meng-Qin Huang, Hong-Lei Wang, Xin-Yu Li, Zi-Xuan Wang, Yong Wu, Jia-Bei Jin, Ji Feng, Zhen-Chang Wang, Guo-Dong Lu, Jing Zhou.

The development of effective and low-toxicity therapies for liver cancer and other malignancies remain an unmet clinical challenge, primarily due to dysregulated cancer cell proliferation and therapeutic resistance. In this study, we demonstrate that the natural compound celastrol effectively overcomes this by inducing a coordinated cell death program through transcription factor EB (TFEB)-mediated lysosomal activation. Mechanistically, celastrol facilitates TFEB nuclear translocation, enhancing lysosomal biogenesis and triggering ferritinophagy. The subsequent release of free iron, in conjunction with celastrol-induced accumulation of reactive oxygen species (ROS), leads to lethal lipid peroxidation and ferroptosis. Furthermore, this peroxidative stress activates the pro-apoptotic protein Bid, cascading the ferroptotic signal into mitochondrial apoptosis. Notably, TFEB overexpression amplifies the anticancer efficacy of celastrol, whereas TFEB knockdown or lysosomal inhibition abrogates celastrol-induced cytotoxicity, confirming the critical role of the lysosomal pathway. Collectively, our study elucidates a novel TFEB‑lysosome‑ferroptosis‑apoptosis axis as the mechanistic foundation for celastrol's anticancer properties, underscoring its therapeutic promise against liver cancer and potentially other malignancies with similar vulnerabilities.

Keywords: Celastrol; Ferroptosis; Lysosome; ROS; transcription factor EB

DOI: https://doi.org/10.1016/j.bcp.2026.117848

Spectrochim Acta A Mol Biomol Spectrosc. 2026 Feb 08. pii: S1386-1425(26)00141-1. [Epub ahead of print]354 127570

Mapping dynamic changes in lysosomal polarity with a sensitive and large stokes shift fluorescent probe.

Ruifang Wang, Rong Li, Peng Lei, Liyun Zhang.

Lysosomal polarity is closely associated with its functional integrity, and its dynamic changes serve as a key indicator for assessing cellular status and the progression of various diseases. However, currently available fluorescent probes for monitoring lysosomal polarity generally suffer from small Stokes shifts and insufficient sensitivity, leading to low signal-to-noise ratios and susceptibility to auto-fluorescence interference, making it difficult to accurately track dynamic fluctuations. To address the above challenge, this study successfully developed a novel lysosome-targeted fluorescent probe PTC. PTC is ingeniously designed based on a strong intramolecular charge transfer (ICT) effect, exhibiting not only high sensitivity to the microenvironmental polarity (showing a good linear relationship between fluorescence intensity and polarity) but also a remarkably large Stokes shift (>165 nm). We successfully achieved high-fidelity imaging of lysosomal polarity, detected autophagy process, and captured in real-time the dynamic evolution of lysosome. This probe provides a powerful chemical tool for in-depth research into the molecular mechanisms of lysosome-related diseases.

Keywords: Fluorescent probe; Large stokes shift; Lysosomal polarity

DOI: https://doi.org/10.1016/j.saa.2026.127570

Adv Drug Deliv Rev. 2026 Feb 23. pii: S0169-409X(26)00071-2. [Epub ahead of print] 115837

Strategies for targeted protein degradation through lysosomal pathways.

Wei Wang, Yuxin Fang, Chunquan Sheng.

While proteolysis-targeting chimeras (PROTACs) represent a breakthrough in targeted protein degradation (TPD), their applicability is restricted by fundamental limitations. Mechanistically, they are mainly limited to proteins with accessible cytosolic domains for ligand binding and ternary complex formation. Physically, the proteasome's narrow pore diameter largely bars folded, oligomeric, or aggregated protein species from entering. These inherent restrictions collectively exclude a broad range of challenging targets, including many membrane and extracellular proteins lacking suitable cytosolic ligands, as well as insoluble aggregates and dysfunctional organelles. Encouragingly, the lysosome offers a versatile alternative pathway, capable of degrading a wide spectrum of macromolecules and cellular structures. Lysosome-engaging TPD strategies have recently gained significant traction, offering the potential to diversify the TPD toolkit, overcome the limitations of PROTACs, and expand the target scope of TPD technologies to encompass a broader range of human diseases. This review aims to comprehensively survey this rapidly advancing field by examining the design principles, demonstrating its potential through case studies, and critically evaluating future opportunities and challenges.

Keywords: Autophagic-lysosomal pathway; Drug discovery; Endosomal–lysosomal pathway; Lysosome-based degradation; Targeted protein degradation

DOI: https://doi.org/10.1016/j.addr.2026.115837