ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023
Polyphyllin D punctures hypertrophic lysosomes to reverse drug resistance of hepatocellular carcinoma by targeting acid sphingomyelinase.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 28 citations in OpenAlex.
- Avobenzone induces intestinal injury by targeting ATG14 and impairing mitophagy.Cell communication and signaling : CCS · 2026Article
- Targeting lysosome-dependent cell death in cancer: towards therapeutic strategies.Biomarker research · 2026Review
- Risperidone induces osteoporosis and neuropsychiatric treatment resistance via SMPD1-lysosome-mediated ferroptosis: dual rescue by active vitamin D analog ED-71.Journal of advanced research · 2026Article
- Identification of METTL3 and PRMT5 as an oncogenic pair for the prognosis and therapeutic targets of colorectal cancer subtype.Clinical epigenetics · 2026Article
- Programmed cell death and risk of diabetic retinopathy: a Mendelian randomization study.Journal of translational medicine · 2026Article
- Polyphyllin B induces ferroptosis in triple-negative breast cancer by inactivating NRF2.Frontiers in pharmacology · 2026Article
- Lysosome-dependent cell death in hepatocellular carcinoma: unlocking the therapeutic potential of natural products.Frontiers in pharmacology · 2026Review
- Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity.Nature communications · 2025Article
- InterPAD is a database of drug-drug interaction between phytochemicals and anticancer drugs.Scientific reports · 2025Article
- BPA: a BERT-based priority annotation strategy for assessing the rationality of aquatic algal protein sequences.Briefings in bioinformatics · 2025Article
- Organellophagy regulates cell death:A potential therapeutic target for inflammatory diseases.Journal of advanced research · 2025Review
- An Insight into Research Advances on Herbal and Phytochemical Approaches to the Management of Hepatocellular Carcinoma from January 2020 to July 2024.Anti-cancer agents in medicinal chemistry · 2025Review
- The role of lipophagy in liver cancer: mechanisms and targeted therapeutic interventions.Frontiers in cell and developmental biology · 2025Review
- Polyphyllin II inhibits thyroid cancer cell growth by simultaneously inhibiting glycolysis and oxidative phosphorylation.Open medicine (Warsaw, Poland) · 2025Article
- Genomic insights into Aspergillus tamarii TPD11: enhancing polyphyllin production and uncovering potential therapeutic applications.BMC genomics · 2024Article
- The role ofHeliyon · 2024Review
- Subcellular Drug Distribution: Exploring Organelle-Specific Characteristics for Enhanced Therapeutic Efficacy.Pharmaceutics · 2024Review
- Programmed cell death in hepatocellular carcinoma: mechanisms and therapeutic prospects.Cell death discovery · 2024Review
- Review
- Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer.Acta pharmaceutica Sinica. B · 2024Review
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypertrophic lysosomes are critical for tumor progression and drug resistance; however, effective and specific lysosome-targeting compounds for cancer therapy are lacking. Here we conducted a lysosomotropic pharmacophore-based in silico screen in a natural product library (2,212 compounds), and identified polyphyllin D (PD) as a novel lysosome-targeted compound. PD treatment was found to cause lysosomal damage, as evidenced by the blockade of autophagic flux, loss of lysophagy, and the release of lysosomal contents, thus exhibiting anticancer effects on hepatocellular carcinoma (HCC) cell both in vitro and in vivo. Closer mechanistic examination revealed that PD suppressed the activity of acid sphingomyelinase (SMPD1), a lysosomal phosphodieserase that catalyzes the hydrolysis of sphingomyelin to produce ceramide and phosphocholine, by directly occupying its surface groove, with Trp148 in SMPD1 acting as a major binding residue; this suppression of SMPD1 activity irreversibly triggers lysosomal injury and initiates lysosome-dependent cell death. Furthermore, PD-enhanced lysosomal membrane permeabilization to release sorafenib, augmenting the anticancer effect of sorafenib both in vivo and in vitro. Overall, our study suggests that PD can potentially be further developed as a novel autophagy inhibitor, and a combination of PD with classical chemotherapeutic anticancer drugs could represent a novel therapeutic strategy for HCC intervention.
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