bims-lycede 2026-04-05 papers

Trends Cell Biol. 2026 Mar 30. pii: S0962-8924(26)00038-3. [Epub ahead of print]

Lysosome: a critical hub for ferroptosis regulation.

Ferroptosis is an iron-dependent programmed cell death that involves lipid peroxidation. Ferroptosis represents a critical process underlying tumorigenesis and multiple pathological disorders. Recently, lysosomes have been found to orchestrate ferroptotic signaling, linking iron metabolism, oxidative homeostasis, and selective autophagy. Furthermore, lysosomal membrane disruption leads to the release of intraluminal iron and cathepsins, thereby facilitating ferroptotic damage, whereas lysosomal exocytosis acts in the opposite direction to limit ferroptosis. Therefore, pharmacological modulation of lysosomal activities could be used to treat drug-resistant tumors or protect normal tissues against ferroptosis-related injuries. In this review, we summarize how lysosomes control ferroptosis, focusing on the regulation through lysosomal contents, pH, degradation processes, and exocytosis. We also discuss possible therapeutics that target lysosomes to modulate ferroptosis-associated diseases.

Keywords: LMP; autophagy; ferritinophagy; ferroptosis; iron; lysosome

DOI: https://doi.org/10.1016/j.tcb.2026.03.007

Methods Cell Biol. 2026 ;pii: S0091-679X(25)00194-3. [Epub ahead of print]204 171-192

Assessment of lysosomal drug sequestration and release using fluorescence microscopy.

Lucille Ferret, Samy Dehissi, Jean Guillon, Karla Alvarez-Valadez, Guido Kroemer, Mojgan Djavaheri-Mergny.

Lysosomotropism refers to the ability of certain basic lipophilic compounds to accumulate in lysosomes via pH partitioning. Various drugs including anticancer agents are trapped in lysosomes, and this process can prevent such drugs from reaching their primary target, thereby limiting their effectiveness. Strategies aimed at preventing drug sequestration or inducing drug release from lysosomes have garnered considerable interest. Chloroquine is a widely used anti-malarial drug that triggers lysosome membrane permeabilization (LMP) to liberate sequestered drugs from these organelles. In this study, we first evaluate the lysosomotropism of various fluorescent anticancer agents in silico. Next, we outline a simple, fast and robust method for the visualization and quantification of their lysosomal sequestration and release by fluorescence microscopy. The method is used on live cells and consists of two steps: (i) visualization of the compounds in lysosomes by analyzing their colocalization with a specific fluorescent lysosomal marker, and (ii) assessment of drug release from lysosomes. Furthermore, we present fluorescence microscopy protocols for monitoring LMP by analyzing the subcellular localization of LGALS3 (Galectin-3), which normally distributes diffusely in the cytoplasm but translocates into lysosomes upon LMP. This can be achieved on fixed cells by detecting endogenous LGALS3 with immunostaining or by the visualization of a transgenic LGALS3-mCherry fusion protein on live cells. Altogether, these methods facilitate qualitative and quantitative fluorescence imaging of lysosomal sequestration and liberation of lysosomotropic drugs.

Keywords: Cancer; Cell biology; Drug release; High-content imaging; LGALS3; Lysosomal membrane permeabilization; Lysosomotropic agents; Resistance to therapy; TFEB; Transcription

DOI: https://doi.org/10.1016/bs.mcb.2025.09.006

Autophagy. 2026 Mar 30. 1-3

Dual pathways of TFEB activation under lysosomal stress: ATG conjugation-dependent and -independent modes.

Takayuki Shima, Shuhei Nakamura.

TFEB (transcription factor EB) regulates the expression of autophagy and lysosomal genes, is activated by various cellular stresses, and plays a key role in maintaining cellular homeostasis. Recent work demonstrates that TFEB is activated during lysosomal damage through two distinct mechanisms: ATG conjugation-dependent and -independent. TFEB activation proceeds sequentially through two modes. In the early ATG conjugation-independent mode (Mode I), APEX1 interacts with TFEB in the nucleus, maintaining its transcriptional activity and protein stability. In the later ATG conjugation-dependent mode (Mode II), CCT7 and TRIP6 translocate to lysosomes and interact with TFEB, modulating its phosphorylation and nuclear localization. Moreover, TFEB regulation induced by other cellular stresses-such as oxidative stress, proteasome inhibition, mitochondrial damage, and DNA damage-also involves either Mode I or Mode II. Our findings provide new insights into a unified understanding of TFEB regulation under diverse cellular stress conditions.

Keywords: Damage; TFEB; lysosome; mitochondria; organelle

DOI: https://doi.org/10.1080/15548627.2026.2642336

J Clin Invest. 2026 Apr 01. pii: e199845. [Epub ahead of print]136(7):

Lysosomal homeostasis at the crossroads of neurodegeneration.

Stefano De Tito, Sharon A Tooze.

Lysosomes function as metabolic control centers that integrate degradation, nutrient sensing, and stress signaling. In neurons, which must maintain proteostasis and energetic balance throughout life, lysosomal homeostasis determines cellular resilience. Emerging evidence identifies lysosomal injury and defective repair as common denominators across neurodegenerative diseases. Damage to the lysosomal membrane caused by oxidative stress, lipid imbalance, or genetic mutations triggers a hierarchical quality control cascade. Early lesions recruit the endosomal sorting complex required for transport (ESCRT) machinery for mechanical resealing, while larger ruptures activate lipid-centered recovery modules. When repair fails, lysophagy eliminates irreparable organelles and a TFEB-dependent transcriptional program regenerates the lysosomal pool. These tightly coupled responses safeguard neurons from catastrophic proteostatic collapse. Their impairment, through mutations in lysosomal proteins, or through aging, produces the lysosomal fragility that underlies Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis/frontotemporal dementia, and Huntington disease. Crosstalk between lysosomes, mitochondria, and ER integrates local damage with systemic metabolic adaptation, while dysregulated lysosomal exocytosis and inflammation propagate pathology. Understanding how ESCRT complexes, lipid transport, and transcriptional renewal cooperate to preserve lysosomal integrity reveals unifying principles of neurodegeneration and defines molecular targets for intervention. Restoring lysosomal repair and renewal offers a rational path toward preventing neuronal loss.

DOI: https://doi.org/10.1172/JCI199845