ArticleAutophagy2021
Discovery of a potent SCAP degrader that ameliorates HFD-induced obesity, hyperlipidemia and insulin resistance via an autophagy-independent lysosomal pathway.
Article in Autophagy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 94 citations in OpenAlex.
- Overexpression of Circular RNA circTTN Promotes Ferroptosis in Sepsis-Induced Cardiomyopathy.Journal of cellular and molecular medicine · 2026Article
- Role of SCAP in regulation of pancreatic homeostasis, pancreatitis, and tumorigenesis.Oncogene · 2026Article
- 4-Hydroxybenzyl Alcohol Mitigates Hyperlipidemia-Associated Depression by Inhibiting Neuroinflammation via the NKIRAS2/NF-κB Pathway.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- SREBP2 regulates CCDC25 expression and promotes tumor metastasis in Triple-Negative Breast Cancer.Oncogenesis · 2026Article
- An oral nanocombinatorial agent exhibits pleiotropic improvement in diabetic nephropathy via modulation of the SCAP/SREBPs pathway.Journal of nanobiotechnology · 2026Article
- GCN5 drives MASLD progression through LXRα/SREBP1c signaling pathway-mediated de novo lipogenesis.Nature communications · 2026Article
- VB-84922 is a small molecule that inhibits ER-to-golgi transport of SREBPs-SCAP complexes.Frontiers in pharmacology · 2026Article
- A moderate lard-included diet reduces fat deposition and inflammation in the adipose tissue.NPJ science of food · 2025Article
- Alternative cleavage and polyadenylation: key regulatory mechanisms in health and disease.RNA biology · 2025Review
- In Vivo Models of Cardiovascular Disease:Biomedicines · 2025Review
- Protective effects of berberine on MASLD: regulation of glucose and lipid metabolism through PI3K/Akt and STING pathways.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- SCAP Interacts with Trim27 to Promote Vascular Neointimal Hyperplasia by Regulating the Stability and Ubiquitination of IκBα.Aging and disease · 2025Article
- Lipid metabolism: the potential therapeutic targets in glioblastoma.Cell death discovery · 2025Review
- Targeting the gut microbiota and lipid metabolism: potential mechanisms of natural products for the treatment of non-alcoholic fatty liver disease.Frontiers in pharmacology · 2025Review
- Exploring Therapeutic Targets for Preventing Cardiac Arrest by Modulating Dyslipidemia and 25-Hydroxyvitamin D Metabolism: A Mendelian Randomization Study.Human mutation · 2025Article
- Protective effect of lycorine hydrochloride against diabetic nephropathy in high-fat diet and streptozotocin-induced diabetic mice.Pharmaceutical science advances · 2024Article
- Lycorine ameliorates liver steatosis, oxidative stress, ferroptosis and intestinal homeostasis imbalance in MASLD mice.Molecular medicine (Cambridge, Mass.) · 2024Article
- Combined metformin and simvastatin therapy inhibits SREBP2 maturation and alters energy metabolism in glioma.Cell death & disease · 2024Article
- Targeted protein degradation: advances in drug discovery and clinical practice.Signal transduction and targeted therapy · 2024Review
- Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.