BAY-876

Selective autophagy relies on multivalent recognition by receptors like SQSTM1/p62 to form aggregates that cluster disperse organelles, undergoing liquid-liquid phase separation to facilitate their clearance and maintain cellular homeostasis. Inspired by this, we present the multivalent nanoparticle-based organelle targeting chimera (NanoTAC^Org) to efficiently degrade organelles by flexibly clustering organelles for sequestration and facilitating targeted recruitment of autophagosomes. NanoTAC^Org, assembled with a PLGA core, lysosomal escape modules, organelle-targeting modules, and LC3B binding modules, is programmed to selectively degrade various organelles, including mitochondria, endoplasmic reticulum, and Golgi apparatus. After endocytosis and lysosomal escape, NanoTAC^Org targets subcellular compartments and mimics p62 aggregate-driven organelle clustering and degradation, without exhibiting the "hook effect". Specifically, NanoTAC^Mito-mediated mitochondrial degradation disrupts oxidative phosphorylation (OXPHOS) while enhancing compensatory glycolysis, thus sensitizing tumor cells to the glucose transporter 1 (GLUT1) inhibitor BAY-876. BAY-876 loaded NanoTAC^Mito potently inhibits tumor growth, recurrence, and metastasis, demonstrating superior therapeutic efficacy by simultaneously targeting OXPHOS and glycolysis. These findings highlight the potential of NanoTAC^Org as a versatile and effective platform for cancer therapy, particularly through organelle-specific degradation and metabolic reprogramming.

In contrast to normal cells, cancer cells predominantly utilise glycolysis for ATP generation under aerobic conditions, facilitating proliferation and metastasis. Targeting glycolysis is effective for cancer treatment. Prodigiosin (PDG) is a natural compound with various bioactivities, including anticancer effects. However, the precise action mechanisms and molecular targets of PDG, which has demonstrated efficacy in regulating glucose metabolism in cancer cells, remain elusive. Here, we aimed to investigate the anti-cancer activity of PDG and mechanism in cancer metabolism. PDG regulated cancer metabolism by suppressing intracellular ATP production rate and levels. It inhibited glycolysis and mitochondrial oxidative phosphorylation, impeding ATP production dependent on both glycolysis and mitochondrial respiration. Moreover, it inhibited cellular glucose uptake by directly interacting with glucose transporter 1 without affecting its mRNA or protein levels in HCT116 cells. We provide insights into the anti-cancer effects of PDG mediated via cancer metabolism regulation, suggesting its therapeutic potential for cancer.