bims-lycede 2025-12-14 papers

Int J Mol Sci. 2025 Nov 29. pii: 11581. [Epub ahead of print]26(23):

The lysosome is no longer viewed as a simple degradative "trash can" of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical "microreactor" that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5-5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective "safe house," yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome's broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody-drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine-thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies.

Keywords: acidic organelles; drug resistance; drug–lysosome interactions; fenton reaction; lysosome; lysosomotropic design; metal-mediated reactive oxygen species; therapeutic design principles

DOI: https://doi.org/10.3390/ijms262311581

Biochemistry (Mosc). 2025 Nov;90(11): 1757-1763

Cysteine Cathepsins and Drug Discovery: Knowns and Unknowns.

Andrey A Zamyatnin.

Cysteine cathepsins are a group of closely related proteolytic enzymes active at low pH. The most well-studied function of these enzymes is protein degradation within lysosomes. However, accumulating evidence suggests that cysteine cathepsins also function at physiological pH levels in other cellular compartments outside lysosomes, as well as in the extracellular space. Many of these extra-lysosomal functions of cysteine cathepsins are typically associated with pathological processes, contributing to conditions such as oncogenesis and metastasis, neurodegenerative diseases, cardiovascular disorders, and autoimmune and inflammatory processes. Consequently, cysteine cathepsins have been proposed as diagnostic and prognostic molecular markers, as well as pharmacological targets. Notably, the pathological processes involving these enzymes often operate independently of their classical lysosomal functions. This work aims to outline key questions, the answers to which could enhance our understanding of the fundamental mechanisms governing the extra-lysosomal functions of cysteine cathepsins. Addressing these questions is also critical for developing novel therapeutic strategies to treat diseases in which cysteine cathepsins play a pathogenic role.

Keywords: cysteine cathepsins; drug development; enzyme inhibitors; papain-like cysteine proteases; pharmacological targets

DOI: https://doi.org/10.1134/S0006297925602205

J Biochem. 2025 Dec 10. pii: mvaf078. [Epub ahead of print]

Recent Advances in the Targeting and Functional Diversity of LAMP-2 Short Tail Variants.

Hideaki Fujita.

LAMP2 is one of the major lysosomal membrane proteins. It contains a large luminal domain, a single transmembrane (TM) domain, and an unusually short cytoplasmic tail composed of only 11 amino acids. Three splicing variants-LAMP-2A, LAMP-2B, and LAMP-2C-share an identical luminal domain but differ in their TM and cytoplasmic tail sequences, resulting in distinct trafficking pathways and functions. Yamaguchi et al. demonstrated that the ultimate target compartments of these isoforms diverge according to the binding affinities of their cytoplasmic tails for μ-subunits of adaptor protein (AP) complexes AP-1, AP-2, AP-3, and AP-4. Intriguingly, each isoform contributes to specific lysosomal functions. It is remarkable that such short cytoplasmic tails not only determine subcellular localization but also underlie the functional diversity of LAMP-2 isoforms.

Keywords: LAMP-2; adaptor protein (AP) complexes; chaperone-mediated autophagy; lysosome; protein trafficking

DOI: https://doi.org/10.1093/jb/mvaf078

Trends Genet. 2025 Dec 05. pii: S0168-9525(25)00287-2. [Epub ahead of print]

Lysosomal activation leaves a lasting memory.

Amaresh Chaturbedi, Charles Lowell Heinke, Siu Sylvia Lee.

Beyond their degradative role, lysosomes help prepare Caenorhabditis elegans offspring for stress. In a recent study, Zhang et al. show that lysosomal activation induces somatic histone H3.3 production, which moves to the germline and is methylated at K79 to transmit longevity. Thus, this work establishes lysosomes as a conduit linking metabolism, chromatin, and epigenetic inheritance.

Keywords: H3.3 (HIS-71); H3K79 methylation; aging; lysosomal lipolysis; transgenerational inheritance

DOI: https://doi.org/10.1016/j.tig.2025.11.005

Autophagy. 2025 Dec 08.

CCPG1-mediated reticulophagy promotes tumorigenesis and cisplatin resistance in bladder cancer.

Yang Dong, Sufang Tian, Xueying Peng, Ping Wang, Xuehong Qian, Chenxi Xie, Rongfu Tu, Xinghuan Wang, Yixian Cui.

Reticulophagy, a selective macroautophagy/autophagy process targeting endoplasmic reticulum fragments via receptors, plays a critical role in cellular homeostasis. This study reveals that CCPG1, a reticulophagy receptor, drives bladder cancer (BLCA) tumorigenesis and confers cisplatin resistance. We observed elevated reticulophagy activity in BLCA cells compared to normal counterparts, particularly under conditions of nutrient stress. CCPG1 expression was significantly upregulated in BLCA patient samples and correlated with poor prognosis. Functional studies demonstrated that CCPG1 knockdown suppressed reticulophagy, leading to decreased cell proliferation and increased apoptosis. Conversely, overexpression of the wild-type CCPG1, but not a MAP1LC3/LC3-binding-deficient variant, rescued reticulophagy and promoted tumor growth. Notably, we found that cisplatin treatment inhibited reticulophagy by downregulating CCPG1 expression through the ATM-CHEK2/Chk2 signaling pathway. CCPG1 knockdown synergistically enhanced cisplatin cytotoxicity to BLCA cells, while CCPG1 overexpression conferred resistance. These findings highlight CCPG1-mediated reticulophagy as a driver of BLCA progression and as a potential prognostic biomarker and therapeutic target.

Keywords: ATM; CHEK2; autophagy; biomarker; endoplasmic reticulum; receptor

DOI: https://doi.org/10.1080/15548627.2025.2601865