Archives of Pharmacal Research最新文献

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment (TME), indicating that immune cell activation is a promising approach. The use of γ-secretase inhibitors (GSIs) to control high Notch signaling activity is currently one of the traditional methods for clinical immunotherapy of HCC. However, the lack of substrate specificity in GSIs often leads to serious side effects. In contrast, a novel small molecule compound, RBPJ inhibitor-1 (RIN1), which selectively blocks the functional interaction between RBPJ and Notch intracellular domain (NICD), has been found to inhibit CD8⁺ T cells exhaustion in HCC effectively. However, its impact on CD4⁺ T cells is still unknown. This study found that RIN1 stimulated T cell IL-17 and IFN-γ secretion, and drove more T cell differentiation towards Th17.1 (CD161⁺, CD183⁺, CD191⁻). Furthermore, RIN1 upregulated T cell STAT3, STAT4, TBX21 protein levels, enhanced STAT3 and RORγt binding to the IL-17 promoter, and facilitated STAT4 and TBX21 enrichment on IFNG promoter. RIN1 also boosted T cell-mediated antitumor immunity and inhibited HCC cells’ epithelial-mesenchymal transition. Notably, IL-17R knockdown in HCC cells partially reverted RIN1-enhanced T cell antitumor effects. In vivo, RIN1 promoted the expression of IL-17 and IFN-γ in CD4⁺ TILs while suppressing PD-1 expression and reducing the frequency of Treg cells, exhibiting tumor growth inhibition. These findings suggested that RIN1 enhances CD4⁺ T cell-mediated antitumor immunity in HCC by modulating gene transcription and cell subset differentiation, highlighting its potential as an immunostimulatory agent (Graphical abstract).

The genus Croton, a member of the Euphorbiaceae family, comprises nearly 1300 species globally, predominantly inhabiting tropical and subtropical regions. Certain species of Croton are renowned for their significant medicinal properties. Diterpenoids, as the principal bioactive constituents of this genus, exhibit a diverse array of biological activities. From 2013 to 2025, a total of 545 newly identified diterpenoids featuring 34 distinct skeletal types, predominantly labdane, clerodane, tigliane, and crotofolane structures, were isolated from 45 Croton species, including several novel frameworks. According to available literature, Croton diterpenoids demonstrate notable anti-inflammatory and anti-tumor properties, with clerodane and tigliane variants showing particularly promising results. Additionally, antimicrobial, anti-proliferative, anti-angiogenic, neuroprotective, insecticidal, and anti-liver fibrotic activities have been reported for various Croton diterpenoids. This review consolidates information on the distribution, chemical structures, potential biosynthetic pathways and biological activities of diterpenoids isolated from Croton species during the specified period.

5-Fluorouracil (5-FU) remains the most commonly used first-line chemotherapeutic agent for the treatment of esophageal cancer (EC), but its therapeutic efficacy is unsatisfactory. In this study, we found that 5% of ESCC cells survived the treatment with high doses of 5-FU for 5 days. Compared to the parental cells, the rapidly acquired drug-tolerant persister (DTP) cells showed enhanced expression of those genes associated with stemness and epithelial-mesenchymal transition. Once 5-FU was removed, the regrown cells regained their sensitivity to 5-FU. Additionally, the transcriptomic profiles analysis showed that the parental and the regrown cells had very similar gene expression profile, while DTP cells showed distinct changes. Significant changes in histone deacetylation pathway were observed in DTP cells. Knockdown of HDAC2/6/9 and BRD4 markedly reduced the formation of DTP cells. We screened our drug library and found that HDAC4/5/6/7 inhibitor TMP269 and BRD2/3/4 inhibitor ABBV-744 showed potent synergistic cytotoxic effects with 5-FU in the parental ESCC cells. Our team then synthesized a new HDAC inhibitor YFF-702 and BET inhibitor C-34, which showed synergistic effects with 5-FU in the parental ESCC cells. Moreover, ABBV-744 and YFF-702 showed synergistic cytotoxic effects with 5-FU in DTP cells. Animal experiments further demonstrated that YFF-702 significantly improved the efficacy of 5-FU in an in vivo tumor model. This current research demonstrates that combining HDAC/BET inhibition with 5-FU may be a promising therapeutic strategy for ESCC patients by targeting 5-FU indued DTP cells.

Resveratrol has been shown to mitigate liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs). However, the precise mechanisms remain incompletely understood. Resveratrol demonstrates therapeutic potential in alleviating liver fibrosis by promoting HSC ferroptosis through the dual regulation of endoplasmic reticulum stress (ERS) and glutamine metabolism, as shown by in vivo and in vitro investigations. In carbon tetrachloride (CCl₄) induced fibrotic mice, resveratrol significantly attenuated liver injury, extracellular matrix (ECM) deposition, and collagen synthesis. Cellular experiments revealed its dose-dependent inhibition of HSC activation via glutathione (GSH) depletion, iron accumulation, and downregulation of GSH peroxidase 4 (GPX4), with ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversing these effects. Mechanistically, resveratrol suppressed activating transcription factor 4 (ATF4) -mediated ERS signaling, subsequently reducing alanine–serine–cysteine transporter 2 (ASCT2) dependent glutamine uptake essential for GSH biosynthesis. Genetic manipulation experiments confirmed the central regulatory role of ATF4, whose overexpression counteracted resveratrol's effects, while ATF4 knockdown or Jumonji domain-containing protein D3 (JMJD3) inhibition epigenetically silenced ASCT2 transcription through enhanced trimethylation of histone H3 at lysine 27 (H3K27me3). These findings revealed a novel pathway by which resveratrol induces HSC ferroptosis through metabolic and epigenetic regulation, offering a multi-targeted strategy against hepatic fibrosis that bridges amino acid metabolism, redox homeostasis, and chromatin remodeling processes.

Cytochrome P450 (CYP) enzymes are crucial for metabolizing various compounds, including therapeutic drugs. Metabolites generated through CYP-mediated pathways have been increasingly recognized as key contributors to the pathogenesis and progression of diverse diseases, particularly cancer. Consequently, ongoing research is examining Food and Drug Administration-approved drugs as potential inhibitors of specific CYP isoforms and characterizing their underlying mechanisms of action. These studies are essential for clarifying how approved drugs alter the metabolic pathways of co-administered agents, thereby influencing therapeutic efficacy and safety outcomes. CYP inhibitors significantly alter substrate metabolism, thereby increasing the risk of drug–drug interactions (DDIs). These interactions pose crucial challenges in clinical practice, necessitating careful evaluation when co-administering medications with similar metabolic pathways. Therefore, this review aims to examine the complex interplay among CYP inhibitors, their substrates, and DDIs in both cancers and non-neoplastic diseases, including allergies, depression, and stroke. The review seeks to minimize adverse outcomes and enhance therapeutic effectiveness by offering a comprehensive understanding of CYP inhibitors.

Boron, a versatile element historically underexplored in medicinal chemistry, has recently garnered prominence for its unique chemical properties that enable the design of innovative therapeutic compounds. The success of boron-containing drugs such as Bortezomib has spurred interest in developing boron-based compounds targeting a variety of tumor-related proteins. This review provides the first target-centric synthesis of boron-containing anticancer agents, integrating structure–activity relationships, binding mode visualizations, and clinical pipeline status across enzyme and receptor targets. Unlike prior reviews focused on chemistry or individual compound classes, it highlights how boron enables reversible covalent inhibition, prodrug activation, and bioisosteric replacement to overcome resistance and selectivity barriers in oncology. This review highlights the current advancements in boron-containing therapeutics, emphasizing their applications in cancer treatment. The ability to form reversible covalent bonds and interact selectively with biomolecules makes it particularly valuable for enzyme and receptor targeting. Moreover, recent developments have introduced boron-based compounds capable of overcoming drug resistance, enhancing selectivity, and minimizing side effects. This review categorizes boron-containing therapeutics into enzyme-targeting and receptor-targeting categories, discussing their mechanisms of action, preclinical and clinical advancements, and future potential. These advancements establish boron-based chemistry as a powerful tool for overcoming limitations of conventional cancer drugs, paving the way for next-generation oncologic therapies with improved specificity and reduced side effects.

Estrogen receptors (ERs) are expressed in approximately 70% of breast cancer patients and serve as pivotal therapeutic targets. ER-targeting agents like selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) have harvested encouraging clinical outcomes. However, the expansion of their clinical utility remains limited by adverse effects, acquired resistance, and suboptimal pharmacokinetic properties. Recent advancements in ER biology have driven the development of novel ER-targeted agents, including third-generation SERMs, oral SERDs, complete ER antagonists, selective ER covalent antagonists, SERM/SERD hybrids, selective human ER partial agonists, and dual-mechanism ER inhibitors. Moreover, innovative technologies, such as proteolysis-targeting chimeras, molecular glue degraders, and lysosome-targeting chimeras have revolutionized ER degradation strategies, offering possibilities to circumvent drug resistance and enhance therapeutic efficacy. Despite these advances, only two ER-targeted drugs have been officially approved to date, indicating the barriers on the road to clinical translation. This review summarizes the recent progresses and challenges in the development of ER-targeted drugs, aiming to offer a perspective into the future of anti-ER therapies in breast cancer management.

Glioblastoma (GBM) is the most aggressive and deadliest type of primary brain tumor, treated with temozolomide (TMZ) as first-line chemotherapy. However, temozolomide resistance remains a critical therapeutic hurdle in GBM, often resulting in treatment failure and tumor recurrence. Here, we aimed to identify an epigenetic target to overcome TMZ resistance in GBM. We established TMZ-resistant GBM cell lines, which exhibited increased expression of resistance markers such as E2F6, ABCG2, and phosphorylated STAT3, and decreased Bax expression. Through KDM inhibitor screening with these cells, we identified KDM4C as a key therapeutic target. Pharmacological inhibition of KDM4C via SD70 significantly reduced the viability, proliferation, and stem-like properties of TMZ-resistant GBM cells. Notably, combination treatment with SD70 and TMZ showed a synergistic effect, restoring TMZ sensitivity. Mechanistically, KDM4C directly bound to the promoter of E2F6, a transcription factor associated with poor prognosis and chemoresistance of GBM. Moreover, genetic and pharmacological inhibition of KDM4C reduced E2F6 expression. Collectively, our findings reveal that KDM4C drives TMZ resistance in GBM by epigenetically upregulating E2F6, and suggest that targeting KDM4C may be a potential approach to overcome TMZ resistance in GBM.

Succinimide motifs are recognized as privileged cores in anticonvulsants and antipsychotics such as phensuximide, ethosuximide, and lurasidone. These succinimides can be readily converted into pharmaceutically important pyrrolidines and γ-lactam scaffolds, making them highly promising compounds in drug discovery. Nitroarenes are also important chemical feedstocks and have attracted increased attention owing to their versatile applications in pharmaceuticals, functional materials, and agricultural pharmacology. Therefore, directly combining succinimides with nitroarenes is a valuable approach for efficiently constructing novel succinimide-linked nitroarene frameworks. We herein report the site-selective addition of the succinimide scaffold to various nitroarenes via nitro-directed ortho-C–H alkylation using maleimides under rhodium(III) catalysis. The versatility of the developed protocol is demonstrated through nitro-group reduction, reductive cyclization of the synthesized products, and selective modifications of the succinimide framework. Mechanistic studies, including deuterium-labeling and kinetic isotope effect experiments, helped elucidate a plausible reaction mechanism.

Osteoarthritis (OA) is characterized by oxidative stress, inflammation, and apoptosis, leading to an imbalance between cartilage extracellular matrix (ECM) synthesis and degradation. Gingerols can regulate multiple biological activities, indicating their therapeutic potential for OA. The present study investigated the feasibility, efficacy, and mechanism of gingerols for OA therapy. Regarding feasibility, gingerol exhibited antioxidant, anti-inflammatory, and antiapoptotic activities for OA therapy, while 10-G exhibited most potent effects among the three gingerols. Regarding efficacy, 10-G upregulated the expression of genes associated with ECM assembly and downregulated the expression of genes involved in ECM disassembly. Mechanistically, 10-G promoted NRF2 nuclear translocation; enhanced antioxidant gene expression; inhibited the phosphorylation of ERK, JNK, P38, RELA, and IKBA; and reduced the expression levels of TP53 and CDKN1A, thereby decreasing the production of inflammatory cytokines and apoptotic regulators. Furthermore, KEAP1 was identified as the direct target of 10-G, with NRF2 confirmed as the key regulatory target. This study demonstrates that 10-G mitigates oxidative stress, inflammation, and apoptosis through the KEAP1-NRF2-ARE axis and simultaneously restores ECM balance to promote cartilage regeneration, establishing its potential as a novel candidate for OA therapy.