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Hepatocellular carcinoma (HCC) remains a notably global health challenge with high mortality rates and poor prognosis. The deregulation of the Hippo signalling pathway, especially the overexpression and activation of downstream effector Yes-associated protein (YAP), has been demonstrated to result in the rapid malignant evolution of HCC. In this context, multiple efforts have been dedicated to targeting YAP for HCC therapy, but effective YAP inhibitors are still lacking. In this study, through a YAP-TEAD (8×GTIIC) luciferase reporter assay, we identified fingolimod, an immunomodulatory drug approved for the treatment of multiple sclerosis, as a novel YAP inhibitor. Fingolimod suppressed the proliferation of HCC cell lines by downregulating the protein levels as well as the trans-activating function of YAP. Overall, our current study not only identifies fingolimod as a novel YAP-targeting in hibitor, but also indicates that this clinically-approved drug could be utilized as a potential and feasible therapeutic drug for HCC.

Disruption of mitochondrial function is observed in multiple drug-induced liver injuries (DILIs), a significant global health threat. However, how the mitochondrial dysfunction occurs and whether maintain mitochondrial homeostasis is beneficial for DILIs remains unclear. Here, we show that defective mitophagy by OPTN (optineurin) ablation causes disrupted mitochondrial homeostasis and aggravates hepatocytes necrosis in DILIs, while OPTN overexpression protects against DILI depending on its mitophagic function. Notably, mass spectrometry analysis identifies a new mitochondrial substrate, GCDH (glutaryl-CoA dehydrogenase), which can be selectively recruited by OPTN for mitophagic degradation, and a new cofactor, VCP (valosin containing protein) that interacts with OPTN to stabilize BECN1 during phagophore assembly, thus boosting OPTN-mediated mitophagy initiation to clear damaged mitochondria and preserve mitochondrial homeostasis in DILIs. Then, the accumulation of OPTN in different DILIs is further validated with a protective effect, and pyridoxine is screened and established to alleviate DILIs by inducing OPTN-mediated mitophagy. Collectively, our findings uncover a dual role of OPTN in mitophagy initiation and implicate the preservation of mitochondrial homeostasis via inducing OPTN-mediated mitophagy as a potential therapeutic approach for DILIs. Abbreviation: AILI: acetaminophen-induced liver injury; ALS: amyotrophic lateral sclerosis; APAP: acetaminophen; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CHX: cycloheximide; Co-IP: co-immunoprecipitation; DILI: drug-induced liver injury; FL: full length; GCDH: glutaryl-CoA dehydrogenase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GO: gene ontology; GSEA: gene set enrichment analysis; GPT/ALT: glutamic – pyruvic transaminase; INH: isoniazid; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MMP: mitochondrial membrane potential; MST: microscale thermophoresis; MT-CO2/COX-II: mitochondrially encoded cytochrome c oxidase II; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20: translocase of outer mitochondrial membrane 20; TSN: toosendanin; VCP: valosin containing protein, WIPI2: WD repeat domain, phosphoinositide interacting 2. [ABSTRACT FROM AUTHOR]

The RAS gene family holds a central position in controlling key cellular activities such as migration, survival, metabolism, and other vital biological processes. The activation of RAS signaling cascades is instrumental in the development of various cancers. Although several RAS inhibitors have gained approval from the US Food and Drug Administration for their substantial antitumor effects, their widespread and severe adverse reactions significantly curtail their practical usage in the clinic. Thus, there exists a pressing need for a comprehensive understanding of these adverse events, ensuring the clinical safety of RAS inhibitors through the establishment of precise management guidelines, suitable intermittent dosing schedules, and innovative combination regimens. This review centers on the evolution of RAS inhibitors in cancer therapy, delving into the common adverse effects associated with these inhibitors, their underlying mechanisms, and the potential strategies for mitigation. [ABSTRACT FROM AUTHOR]

Regorafenib, an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor tyrosine kinases, has been approved for the treatment of metastatic colorectal cancer, gastrointestinal stromal tumors, and hepatocellular carcinoma by the US Food and Drug Administration and European Medicines Agency. However, regorafenib-induced cardiotoxicity increases the risk of mortality. Despite reports that regorafenib can cause mitochondrial dysfunction in cardiomyocytes, the molecular mechanism of regorafenib-induced cardiotoxicity is much less known and there is an urgent need for intervention strategies. Here, we treated mice with vehicle or 200 mg/kg regorafenib daily for 42 d by gavage or treated cardiomyocyte lines with 8, 16, or 32 μM regorafenib, and we found that regorafenib could cause apoptosis, mitochondrial injury, and DNA damage in cardiomyocytes. Mechanistically, regorafenib can reduce the expression of EPHA2, which inhibits AKT signaling, leading to cardiomyocyte apoptosis and cardiotoxicity. In addition, we showed that recovering EPHA2 expression via plasmid-induced overexpression of EPHA2 or schisandrin C, a natural product, could prevent regorafenib-induced cardiotoxicity. These findings demonstrated that regorafenib causes cardiomyocyte apoptosis and cardiac injury by reducing the expression of EPHA2 and schisandrin C could prevent regorafenib-induced cardiotoxicity by recovering EPHA2 expression, which provides a potential management strategy for regorafenib-induced cardiotoxicity and will benefit the safe application of regorafenib in clinic. [ABSTRACT FROM AUTHOR]

The intracellular distribution and transportation process are essential for maintaining PD‐L1 (programmed death‐ligand 1) expression, and intervening in this cellular process may provide promising therapeutic strategies. Here, through a cell‐based high content screening, it is found that the ABCB1 (ATP binding cassette subfamily B member 1) modulator zosuquidar dramatically suppresses PD‐L1 expression by triggering its autophagic degradation. Mechanistically, ABCB1 interacts with PD‐L1 and impairs COP II‐mediated PD‐L1 transport from ER (endoplasmic reticulum) to Golgi apparatus. The treatment of zosuquidar enhances ABCB1‐PD‐L1 interaction and leads the ER retention of PD‐L1, which is subsequently degraded in the SQSTM1‐dependent selective autophagy pathway. In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD‐L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD‐L1 degradation in the early secretory pathway. [ABSTRACT FROM AUTHOR]