bims-lycede 2026-02-15 papers

Int J Mol Sci. 2026 Feb 03. pii: 1515. [Epub ahead of print]27(3):

Pathogen-Induced Lysosomal Membrane Permeabilization: A Critical Interface Between Host Defense and Cell Death.

Xiao Liu, Zhan Li, Yuru Hu, Tao Li, Hui Wang.

During pathogen infection, lysosomes are not only pivotal targets exploited by pathogens to evade host defenses and induce cell death, but also an essential frontline of host protection that restricts infection by degrading invading microbes and repairing membrane damage. A broad spectrum of pathogens-including bacteria, viruses, protozoa, and fungi-can trigger lysosomal membrane permeabilization (LMP), resulting in the leakage of lysosomal contents into the cytosol. The released lysosomal factors can selectively activate distinct cell-death programs, including apoptosis, pyroptosis, ferroptosis, and necroptosis. These cell-death processes may limit pathogen dissemination by eliminating infected cells, yet they can also exacerbate disease through excessive inflammatory responses and tissue injury. In this review, we highlight recent advances and systematically discuss the determinants of lysosomal membrane stability, methods for detecting LMP, and LMP-driven cell-death modalities, and we summarize the mechanisms and consequences of pathogen-induced LMP.

Keywords: cathepsin; cell death; lysosomal membrane permeabilization; lysosome; pathogen infection

DOI: https://doi.org/10.3390/ijms27031515

Int J Pharm. 2026 Feb 06. pii: S0378-5173(26)00099-2. [Epub ahead of print]692 126651

Engineering lysosomal collapse for cancer therapy: From mechanistic insights to nanotherapeutic innovations.

Weidong Fei, Wenqiang Qian, Yu Xin, Yunxi Liu, Xiaodong Wu, Xuwei Zhou, Ying Zhou, Xudong Fan, Yiqing Ye, Caihong Zheng.

BACKGROUND: Lysosomes are markedly altered in tumor cells, exhibiting increased number and size, enhanced acidification, elevated cathepsin activity, and remodeled ion channel composition. These adaptations confer heightened degradative capacity and metabolic plasticity, supporting tumor survival, progression, and therapeutic resistance. Beyond their classical catabolic role, lysosomes function as central hubs for nutrient sensing, stress adaptation, and transcriptional regulation, making lysosomal integrity an emerging vulnerability in cancer therapy.
AIM: This review aims to elucidate the therapeutic potential of inducing lysosomal collapse as an anticancer strategy, with a particular focus on recent nanotherapeutic approaches designed to precisely disrupt lysosomal function.
METHODS: This study systematically summarizes current knowledge on lysosomal structure and function in tumor cells and analyzes preclinical studies that exploit lysosomal destabilization for cancer treatment. Nanotherapeutic strategies targeting lysosomes are categorized according to their underlying mechanisms, including gas generation-mediated blasting, osmotic swelling, fiber-induced expansion, oxidative membrane damage, and direct phospholipid bilayer disruption. For each strategy, the design rationale, mechanistic basis, and representative experimental outcomes are critically evaluated.
RESULTS: Accumulating evidence demonstrates that controlled lysosomal membrane permeabilization or rupture can effectively induce tumor cell death, reverse drug resistance, suppress metastasis, and alleviate immune evasion. Nanotherapeutic platforms enable spatially and temporally precise lysosomal disruption, enhancing antitumor efficacy while minimizing off-target toxicity. Comparative analysis reveals distinct advantages and limitations among different lysosome-targeting strategies, underscoring the importance of rational nanomaterial design.
CONCLUSIONS: These advances establish lysosomes as central regulators of tumor biology and promising therapeutic "death triggers". Lysosome-targeted nanotherapeutics represent a powerful and versatile approach for overcoming major barriers in cancer treatment, offering new opportunities for precise, effective, and mechanism-driven anticancer interventions.

Keywords: Cancer; Collapse; Lysosome; Membrane; Nanotherapeutic

DOI: https://doi.org/10.1016/j.ijpharm.2026.126651

Autophagy. 2026 Feb 09.

AMPK promotes TFEB transcriptional activity through dephosphorylation at both MTORC1-dependent and -independent sites.

Florentina Negoita, Conchita Fraguas Bringas, Kristina Hellberg, Katarzyna M Luda, Hongling Liu, Zhiyuan Li, Joyceline Cuenco, Jin-Feng Zhao, Gajanan Sathe, Ian G Ganley, Gopal P Sapkota, Kei Sakamoto.

TFEB (transcription factor EB) is a critical regulator of lysosomal biogenesis, macroautophagy/autophagy and energy homeostasis through controlling expression of genes belonging to the coordinated lysosomal expression and regulation network. AMP-activated protein kinase (AMPK) has been reported to phosphorylate TFEB at three conserved C-terminal serine residues (S466, S467, S469) and these phosphorylation events were reported to be essential for transcriptional activation of TFEB. In sharp contrast to this proposition, we demonstrate that AMPK activation leads to the dephosphorylation of the C-terminal sites. We show that a synthetic peptide encompassing the C-terminal serine residues of TFEB is a poor substrate of AMPK in vitro. Treatment of cells with an AMPK activator (MK-8722), glucose deprivation or MTOR inhibitor (torin1) robustly dephosphorylated TFEB not only at the MTORC1-targeted N-terminal serine sites, but also at the C-terminal sites. Loss of function of AMPK abrogated MK-8722- but not torin1-induced dephosphorylation and induction of the TFEB target genes.

Keywords: BAY-3827; MK-8722; MTOR; TFE3; coordinated lysosomal expression and regulation; reversible phosphorylation

DOI: https://doi.org/10.1080/15548627.2026.2629720