Background: Macrophage-mediated cancer cell phagocytosis has demonstrated considerable therapeutic potential. While the initiation of phagocytosis, facilitated by interactions between cancer cell surface signals and macrophage receptors, has been characterized, the mechanisms underlying its sustentation and attenuation post-initiation remain poorly understood. Methods: Through comprehensive phosphoproteomic profiling, we interrogated the temporal evolution of the phosphorylation profiles within macrophages during cancer cell phagocytosis. Results: Our findings reveal that activation of the mTOR pathway occurs following the initiation of phagocytosis and is crucial in sustaining phagocytosis of cancer cells. mTOR inhibition impaired the phagocytic capacity, but not affinity, of the macrophages toward the cancer cells by delaying phagosome maturation and impeding the transition between non-phagocytic and phagocytic states of macrophages. Conclusions: Our findings delineate the intricate landscape of macrophage phagocytosis and highlight the pivotal role of the mTOR pathway in mediating this process, offering valuable mechanistic insights for therapeutic interventions.

Oncogenic transformation drives adaptive changes in a growing tumor that affect the cellular organization of cancerous cells, resulting in the loss of specialized cellular functions in the polarized compartmentalization of cells. The resulting altered metabolic and morphological patterns are used clinically as diagnostic markers. This review recapitulates the known functions of actin, microtubules and the γ-tubulin meshwork in orchestrating cell metabolism and functional cellular asymmetry.

The disruption of microtubule dynamics serves as a pivotal strategy for eliminating tumor cells, despite its accompanying toxicities affecting non‐tumor cells. This study investigates the potential of selectively targeting γ‐tubulin1 (TUBG1) as a therapeutic strategy in cancer treatment. By elucidating the TUBG1–E2F1–retinoblastoma protein (RB1) network, we introduce a novel compound, 4‐(6‐((3‐Methoxyphenyl)amino)pyrimidin‐4‐yl)‐N,N‐dimethylbenzenamine, (L12). L12 treatment enhanced RB1 expression and selectively targeted cells with impaired RB1 signaling, while reduced E2F1 expression attenuated its cytotoxicity. Furthermore, L12‐mediated cytotoxicity depends on an E2F1‐mediated upregulation of procaspase 3 expression, highlighting the role of E2F1 in the apoptotic response. Unlike traditional tubulin‐targeting agents, L12's specificity for tumor cells lies in its inhibitory effects on TUBG1, without affecting the second human isoform of TUBGs, TUBG2. Despite its interaction with specific kinases, the concentrations required for antitumor effects are 100‐fold lower than those influencing kinase activities. Subsequent investigations underscore L12's reduced neuronal axonal toxicity compared to vincristine. Lastly, L12 demonstrates promising results in inhibiting tumor growth in xenografted small cell lung cancer models, demonstrating potential specificity toward tumor cells while minimizing adverse effects on healthy tissues. This research emphasizes the potential of TUBG1 inhibitors as a promising advancement in personalized chemotherapy approaches and their potential as a groundbreaking treatment for various cancers.

Background: Valproic acid (VPA)-induced hepatotoxicity is among the most common and severe adverse drug reactions, limiting its clinical application. Recent studies have suggested that activating the farnesoid X receptor (FXR) could be a promising therapeutic approach to alleviate VPA-induced hepatotoxicity; however, related research remains limited. Objective: This study aims to comprehensively investigate the mechanisms underlying FXR activation by obeticholic acid (OCA) for the treatment of VPA-induced hepatotoxicity. Methods: Network pharmacology was performed to identify potential targets and pathways underlying the amelioration of VPA-induced hepatotoxicity by OCA. The identified pathways were validated through GEO data analysis, and the affinities between OCA and potential key targets were predicted using molecular docking as well as molecular dynamics simulations. Results: A total of 462 targets associated with VPA-induced hepatotoxicity and 288 targets of OCA were identified, with 81 shared targets. KEGG pathway and GO enrichment analysis indicated that the effect of OCA on VPA-induced hepatotoxicity primarily involved lipid metabolism, as well as oxidative stress and inflammation. The results from GEO data analysis, molecular docking, and molecular dynamics simulations revealed a close association between bile secretion, the PPAR signaling pathway, and the treatment of VPA-induced hepatotoxicity by OCA. Conclusion: Our findings suggest that OCA exhibits potential therapeutic efficacy against VPAinduced hepatotoxicity through multiple targets and pathways, thereby highlighting the therapeutic potential of FXR as a target for treating VPA-induced hepatotoxicity.