Sorafenib sensitization in tumor therapy by iron overload and AMPK activation

Sorafenib,as a first-line drug for advanced hepatocellular carcinoma(HCC),could trigger ferroptosis by inhibiting cystine/glutamate transporter.However,low-level intracellular iron and insufficient activation of adenosine monophosphate(AMP)-activated protein kinase(AMPK)confer impaired response to sorafenib.In this study,a unique sorafenib nanocomposite dexterously modified with Fe-Material of Institut Lavoisier(sora@Fe-MIL)was synthesized to escalate intracellular iron level and activate AMPK,further potentiating the ferroptotic effect of sorafenib.Remarkably,this strategic deployment of sora@Fe-MIL triggered an extensive demise of cancer cells,while manifesting negligible deleterious impact on normal cells.Two prominent ferroptosis biomarkers,glutathione peroxidase 4(GPX4)and solute carrier family 7 member 11(SLC7A11),underwent pronounced downregulation,underscoring the efficacy of this strategy in inducing ferroptosis.Furthermore,the bioactivity of AMPK was considerably elevated,and its downstream targets were conspicuously inhibited by the treatment with sora@Fe-MIL.Using orthotopic HCC animal models,we observed a substantial suppression of primary in situ tumor growth,and ribonucleic acid(RNA)sequencing elucidated an elevated degree of ferroptosis and AMPK activation with the treatment of sora@Fe-MIL.In conclusion,we proposed that the meticulously designed strategy for secure and efficacious iron release and AMPK activation could significantly potentiate the ferroptotic impact of sorafenib,thus resuscitating its therapeutic response in HCC patients.

Phytic acid-based nanomedicine against mTOR represses lipogenesis and immune response for metabolic dysfunction-associated steatohepatitis therapy

Metabolic dysfunction-associated steatohepatitis(MASH)is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses.Recent studies have indicated that the activation of the mammalian(or mechanistic)target of rapamycin(mTOR)signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment.Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR,their poor specificity and side effects limit their clinical application in MASH treatment.Phytic acid(PA),as an endogenous and natural antioxidant in the liver,presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH.In this study,considering the unique phosphate-rich structure of PA,we developed a cerium-PA(CePA)nanocom-plex by combining PA with cerium ions possessing phosphodiesterase activity.CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups,thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1(SREBP1)regulation axis.The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice.Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function,making it a promising candidate for MASH and other mTOR-related disease treatments.