natural-products-inhibiting-necroptosis-molecular-mechanisms

Natural Products Inhibiting Necroptosis: Molecular Mechanisms and Therapeutic Opportunities

Necroptosis is a genetically regulated form of necrotic cell death initiated by diverse signals, including death receptor ligands, which activate the ...

Chengdu University of Traditional Chinese Medicine

The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.

Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates.

Correction: Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates.

Necroptosis exacerbates ulcerative colitis (UC) by disrupting intestinal barriers and promoting necroinflammation. Heat shock protein 90 (HSP90) regulates receptor-interacting protein kinase 1/3 (RIPK1/3) activity through its chaperone function, thereby participating in necroptosis and emerging as a potential therapeutic target for its inhibition in UC therapy. Costunolide (CTL), a principal sesquiterpene lactone from Aucklandia lappa, has poorly defined mechanisms in UC treatment. This study aimed to elucidate CTL's role in necroptosis inhibition and UC therapy by targeting HSP90.

Article	Year
Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates. Cell death & disease\| PubMed ID: 39349454	2024
Correction: Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates. Cell death & disease\| PubMed ID: 39557827	2024
Covalently targeting HSP90 with a natural small-molecule costunolide to inhibit necroptosis and ulcerative colitis. International immunopharmacology\| PubMed ID: 41687519	2026

Yuying Shi

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