Andrographolide Promotes Ferroptosis in Pancreatic Cancer via Targeting and Activating <scp>HSP90</scp> / <scp>GPX4</scp> Ubiquitination

ABSTRACT Pancreatic adenocarcinoma accounts for 90% of pancreatic cancer cases, the deadliest kind. PC patients' poor immunotherapy, chemotherapy, and other responses lead to a generally failed treatment strategy. Thus, understanding molecular processes is essential for creating novel PC therapies. The natural chemical andrographolide (ADG) from Andrographis paniculata shows anticancer properties against various cancer types. The method by which ADG fights pancreatic cancer is unknown. In PC cell lines, ADG inhibited cell proliferation and migration, caused G0/G1 phase arrest, and caused cell death due to reactive oxygen species, iron accumulation, malondialdehyde production, and glutathione (GSH) exhaustion. Ferrostatin‐1 inhibited ADG‐induced cell death. A molecular docking investigation demonstrated that ADG directly binds to heat shock protein 90 (HSP90). ADG suppresses HSP90 expression, and tanespimycin prevents ADG‐induced cytotoxicity, showing that HSP90 is ADG's main target in activating intracellular activities. Tests using immunoprecipitation, degradation, and in vitro ubiquitination showed that the ADG‐HSP90 pair targeted and broke down glutathione peroxidase 4 (GPX4), allowing it to be tagged for destruction. ADG also reduced cell development, caused apoptosis, increased reactive oxygen species and iron, synthesized malondialdehyde, depleted glutathione, and ubiquitinated and degraded GPX4. In subcutaneous in vivo tumors, ferroptosis caused by ADG inhibits tumor development. HSP90 is a new ADG target. After connecting to and complexing with HSP90, ADG targeted and deleted GPX4, triggering ferroptosis in PC. The findings strongly suggest that ADG may treat PC. ADG's pharmacokinetics and other effects must be studied in patients' clinical trials to make it a pancreatic cancer therapy option.