Novel Covalent Probe Selectively Targeting Glutathione Peroxidase 4 In Vivo: Potential Applications in Pancreatic Cancer Therapy.

Glutathione peroxidase 4 (GPX4) emerges as a promising target for the treatment of therapy-resistant cancer through ferroptosis. Thus, there is a broad interest in the development of GPX4 inhibitors. However, a majority of reported GPX4 inhibitors utilize chloroacetamide as a reactive electrophilic warhead, and the selectivity and pharmacokinetic properties still need to be improved. Herein, we developed a compound library based on a novel electrophilic warhead, the sulfonyl ynamide, and executed phenotypic screening against pancreatic cancer cell lines. Notably, one compound A16 exhibiting potent cell toxicity was identified. Further chemical proteomics investigations have demonstrated that A16 specifically targets GPX4 under both in situ and in vivo conditions, inducing ferroptosis. Importantly, A16 exhibited superior selectivity and potency compared to reported GPX4 inhibitors, ML210 and ML162. This provides the structural diversity of tool probes for unraveling the fundamental biology of GPX4 and exploring the therapeutic potential of pancreatic cancer via ferroptosis induction.

Rapid In Situ Deposition of Iron-Chelated Polydopamine Coating on the Polyacrylamide Hydrogel Dressings for Combined Photothermal and Chemodynamic Therapy of Skin Wound Infection.

Pathogenic bacterial infections of skin wounds have caused a significant threat to clinical treatment and human life safety. Here, we develop a bactericidal hydrogel dressing consisting of a polyacrylamide (PAM) hydrogel framework with in situ surface-deposition of iron-dopped polydopamine (FePDA). The prepared hydrogel dressing (FePDA-PAM) has a compact surface, good tensile strength, and excellent elastic recovery ability. The introduction of Fe3+ ions improve the photothermal therapy (PTT) efficiency of the PDA and endow the hydrogel dressing with chemodynamic therapy (CDT) properties. In vitro experiments show that the antibacterial effect of FePDA-PAM hydrogel on Staphylococcus aureus reach nearly 100% under the combined action of H2O2 and 808 nm near-infrared (NIR) laser, indicating an excellent combined antibacterial property of PTT and CDT. Furthermore, the FePDA-PAM + H2O2 + NIR treatment group in the in vivo antibacterial experiments displays lowest relative wound area and optimal wound healing within 5 days of treatment, thereby indicating the intensive skin wound disinfection. To summarize, the FePDA-PAM hydrogel has simple preparation and good biosafety. It may serve as a potential wound dressing for the combined PTT/CDT dual-mode antibacterial therapy.

An Ultrasmall Fe3 O4 -Decorated Polydopamine Hybrid Nanozyme Enables Continuous Conversion of Oxygen into Toxic Hydroxyl Radical via GSH-Depleted Cascade Redox Reactions for Intensive Wound Disinfection.

Nanozyme-based chemodynamic therapy (CDT) for fighting bacterial infections faces several major obstacles including low hydrogen peroxide (H2 O2 ) level, over-expressed glutathione (GSH) in infected sites, and inevitable damage to healthy tissue with abundant nonlocalized nanozymes. Herein, a smart ultrasmall Fe3 O4 -decorated polydopamine (PDA/Fe3 O4 ) hybrid nanozyme is demonstrated that continuously converts oxygen into highly toxic hydroxyl radical (•OH) via GSH-depleted cascade redox reactions for CDT-mediated bacterial elimination and intensive wound disinfection. In this system, photonic hyperthermia of PDA/Fe3 O4 nanozymes can not only directly damage bacteria, but also improve the horseradish peroxidase-like activity of Fe3 O4 decorated for CDT. Surprisingly, through photothermal-enhanced cascade catalytic reactions, PDA/Fe3 O4 nanozymes can consume endogenous GSH for disrupting cellular redox homeostasis and simultaneously provide abundant H2 O2 for improving •OH generation, ultimately enhancing the antibacterial performance of CDT. Such PDA/Fe3 O4 can bind with bacterial cells, and reveals excellent antibacterial property against both Staphylococcus aureus and Escherichia coli. Most interestingly, PDA/Fe3 O4 nanozymes can be strongly retained in infected sites by an external magnet for localized long-term in vivo CDT and show minimal toxicity to healthy tissues and organs. This work presents an effective strategy to magnetically retain the therapeutic nanozymes in infected sites for highly efficient CDT with good biosafety.

Mosaic Mutant Analysis Identifies PDGFRα/PDGFRß as Negative Regulators of Adipogenesis.

Adipocyte progenitors (APs) express platelet-derived growth factor receptors (PDGFRs), PDGFRα and PDGFRß. Elevated PDGFRα signaling inhibits adipogenesis and promotes fibrosis; however, the function of PDGFRs in APs remains unclear. We combined lineage tracing and functional analyses in a sequential dual-recombinase approach that creates mosaic Pdgfr mutant cells by Cre/lox recombination with a linked Flp/frt reporter to track individual cell fates. Using mosaic lineage labeling, we show that adipocytes are derived from the Pdgfra lineage during postnatal growth and adulthood. In contrast, adipocytes are only derived from the mosaic Pdgfrb lineage during postnatal growth. Functionally, postnatal mosaic deletion of PDGFRα enhances adipogenesis and adult deletion enhances ß3-adrenergic-receptor-induced beige adipocyte formation. Mosaic deletion of PDGFRß also enhances white, brown, and beige adipogenesis. These data show that both PDGFRs are cell-autonomous inhibitors of adipocyte differentiation and implicate downregulation of PDGF signaling as a critical event in the transition from AP to adipocyte.