Search Results (910)

Background: Aberrant glycosylation is closely associated with tumor progression, changes in the tumor microenvironment, and chemoresistance. This study aimed to identify prognostic sialylation-related genes in bladder cancer and define the role of ST3GAL6 in gemcitabine–cisplatin resistance. Methods: Molecular subtype analysis, prognostic analysis, and risk model construction were performed for sialylation-related genes using transcriptomic data and clinical information from the TCGA database. GC-resistant bladder cancer cell models were established for transcriptomic sequencing and untargeted metabolomic analysis. Cell proliferation and drug sensitivity assays were performed to evaluate the function of ST3GAL6. The regulatory relationship between IGF2BP3, ST3GAL6, and the PI3K pathway was further assessed by combining database analysis with molecular experiments. Results: Sialylation-related molecular patterns were associated with patient prognosis and tumor microenvironment features, particularly fibroblast-related characteristics, in bladder cancer. The key model gene ST3GAL6 was upregulated in bladder cancer tissues and was closely associated with prognosis. In GC-resistant bladder cancer cells, ST3GAL6 expression was significantly increased and accompanied by enhanced sialylation activity. ST3GAL6 promoted bladder cancer cell proliferation and reduced sensitivity to cisplatin and gemcitabine, at least in part through the PI3K-AKT-mTOR pathway. IGF2BP3 was also upregulated in resistant cells, is positively correlated with ST3GAL6, and may help maintain ST3GAL6’s expression by stabilizing its mRNA. Conclusions: Our findings suggest that aberrant sialylation is involved in bladder cancer progression and GC resistance. The IGF2BP3-ST3GAL6-PI3K/AKT/mTOR signaling axis may contribute to this process and may serve as a potential biomarker and therapeutic target in bladder cancer. Full article

Hypoxia is a prevalent pathophysiological condition. Prolonged exposure to hypobaric hypoxia can lead to maladaptation, increasing the risk of chronic hypoxic diseases such as high-altitude polycythemia (HAPC). Dauricine, an alkaloid derived from the root of Menispermum dauricum DC, has been demonstrated to possess anti-hypoxic properties; however, its underlying molecular mechanisms remain elusive. In this study, a potential multi-target anti-hypoxic mechanism of dauricine was proposed and computationally evaluated using an integrated approach combining network pharmacology, molecular docking, and molecular dynamics simulations. Common targets between dauricine and hypoxia-related genes were identified through network pharmacology screening. A protein–protein interaction (PPI) network was constructed to identify core targets, followed by Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Molecular docking was subsequently employed to evaluate the binding affinities between dauricine and the candidate core targets, while molecular dynamics simulations were performed to assess the dynamic stability of the resulting complexes. Additionally, the drug-likeness and safety profiles of dauricine were assessed. The results suggest that dauricine may exert its anti-hypoxic effects by modulating candidate core targets, including ESR1, PIK3CA, and MTOR, and by acting on key signaling pathways such as PI3K-Akt, MAPK, and mTOR. This study provides a theoretical foundation for the further investigation of dauricine as a multi-target candidate for intervention in hypoxia and establishes a bioinformatics basis for subsequent experimental validation. Full article

Background: Neuroinflammation and gut–brain axis (GBX) dysregulation are key pathological drivers of stress-related neuropsychiatric disorders. Zhi-Zi-Chi Decoction (ZZCD), a classic Traditional Chinese Medicine (TCM) formula, has been clinically used to alleviate mental disturbances via the TCM principle of “clearing heat and relieving restlessness.” Still, its modern neuroprotective mechanisms, especially its links to gut microbiota and central signaling pathways, remain incompletely elucidated. Purpose: This study aimed to systematically investigate the therapeutic effects of ZZCD on chronic restraint stress (CRS)-induced neurodysfunction in mice and clarify its mechanisms from the perspectives of TCM theory, material basis, gut microbiota–metabolite axis, and central signaling pathways. Method: CRS mice were treated with ZZCD or protocatechuic acid. Behavioral tests evaluated depression- and anxiety-like behaviors. UHPLC-Q-TOF/MS identified ZZCD’s chemical constituents; 16S rRNA sequencing and untargeted metabolomics analyzed gut microbiota and metabolite changes. Western blot, immunofluorescence, and proteomics examined neuroinflammation, microglial polarization, and signaling pathway activity (PI3K/Akt/mTOR, AMPK). Results: ZZCD reversed CRS-induced depression- and anxiety-like behaviors and suppressed neuroinflammation. Mechanistically, UHPLC-Q-TOF/MS identified 424 ZZCD constituents, with prenol lipids, organooxygen compounds, and flavonoids as the most abundant. ZZCD reversed CRS-induced imbalance in gut microbiota, reducing pro-inflammatory Prevotella and enriching beneficial Lactobacillus, and mediated the enrichment of the prebiotic metabolite PCA in colonic and serum samples, which crossed the blood–brain barrier (BBB) to exert neuroprotection. Additionally, ZZCD and PCA normalized the PI3K/Akt/mTOR pathway and activated AMPK, promoting M2 microglial polarization and restoring synaptic plasticity. Conclusions: ZZCD exerts antidepressant effects by a gut-microbiota-dependent modulation of PCA-PI3K/Akt/mTOR and AMPK dual axes that converts microglia from M1 to M2, providing ethnopharmacological evidence and a mechanistic rationale for its clinical application in major depressive disorder. Full article

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality, with poor survival outcomes despite advances in surgery, chemotherapy, targeted therapy, and immunotherapy. The tumor microenvironment (TME) plays a central role in sustaining tumor growth, immune evasion, and systemic metabolic dysfunction. In this study, we performed an integrative analysis of differentially expressed microRNAs (miRNAs) to uncover their contributions to dysregulated signaling networks in NSCLC. hsa-miR-486-5p was identified as a prominent differentially expressed candidate miRNA. Using mathematical modeling and regression-based reduction, we identified Forkhead Box O1 (FOXO1) and Unc-51 like Autophagy Activating Kinase 2 (ULK2) as critical regulatory nodes that integrate oncogenic signaling with cellular homeostasis. Aberrant expression of hsa-miR-486-5p was found to modulate pathways including PI3K/AKT/mTOR, NF-κB, and JAK-STAT3, thereby promoting tumor progression and secretion of inflammatory cytokines. These cytokines, viz., IL-6, TNF-α, and IL-1β, activate muscle-specific protein degradation pathways through E3 ubiquitin ligases TRIM63 and FBXO32, linking NSCLC progression to cancer-associated sarcopenia. Quasipotential landscape analysis further revealed dynamic phenotypic transitions between stable and unstable states, highlighting the adaptability of tumor–host interactions. Collectively, our findings demonstrate that miRNA-mediated regulatory networks not only drive NSCLC progression and inflammation but also contribute to systemic muscle wasting. These insights emphasize the need for novel therapeutic strategies, including RNA-based interventions, to overcome resistance, improve survival, and address the metabolic complications associated with NSCLC. Full article

Bovine viral diarrhea virus (BVDV), a significant global pathogen threatening cattle industries worldwide, presents substantial challenges for disease control. Its ability to infect cattle across all age groups, coupled with incompletely understood transmission mechanisms, complicates prevention and treatment strategies. We previously reported that BVDV induced tunneling nanotubes (TNTs)—F-actin-rich cytoplasmic connections between adjacent cells—and utilizes these structures for intercellular transmission. In this study, we used lentiviral transfection to express various structural and non-structural proteins of BVDV and identified NS5A as a critical viral protein that induces the formation of TNTs. RNA-seq analysis revealed that CKAP2, a host protein, plays a key role in TNT generation, with the PI3K/AKT/mTOR signaling pathway being essential for this process. Further investigation demonstrated that CKAP2 interacts with BVDV NS5A, triggering the activation of the PI3K/AKT/mTOR pathway, thereby promoting TNT formation and enhancing viral dissemination. Our data highlight a previously unknown mechanism of BVDV spreading and replication, which could have significant implications for within-host spread and immune evasion. Full article

C. asiatica (L.) Urban is a medicinal plant widely used in traditional Asian medicine with potential geroprotective properties. Its major bioactive compounds—including asiaticoside, madecassoside, asiatic acid, and madecassic acid—exhibit antioxidant, anti-inflammatory, regenerative, neuroprotective, and cytoprotective activities. Experimental studies demonstrate modulation of signaling pathways involved in oxidative stress, inflammation, apoptosis, extracellular matrix remodeling, and cellular survival, including NF-κB, PI3K/Akt/mTOR, MAPK, Nrf2/HO-1, and TGF-β/Smad pathways. Preclinical evidence further indicates attenuation of cellular senescence, improvement of mitochondrial function, enhanced collagen synthesis, and regulation of cytokine production. In experimental models, C. asiatica has shown beneficial effects on wound healing, skin aging, neuroinflammation, β-amyloid aggregation, neuroplasticity, metabolic dysfunction, and vascular protection. Preliminary preclinical findings also suggest possible effects on telomerase activity and telomere maintenance. However, clinical translation remains limited due to insufficient randomized controlled trials, low oral bioavailability of triterpenoids, variability in extract standardization, and limited pharmacokinetic and long-term safety data. This narrative review summarizes the phytochemistry, molecular mechanisms, pharmacological activities, and potential geroprotective applications of c. asiatica, highlighting its translational relevance in healthy aging and age-related disorders while emphasizing the need for standardized clinical studies. Full article

Background: Prostate cancer (PCa) is the most commonly diagnosed malignancy in men and a leading cause of cancer-related mortality worldwide. Growing evidence indicates that metabolic syndrome components, including obesity, insulin resistance, and hyperglycemia, contribute to PCa development, and progression to more aggressive form. At the same time, standard treatments such as androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) significantly improve oncologic outcomes but are associated with adverse metabolic effects, including increased fat mass, insulin resistance, and sarcopenia, potentially worsening patients’ overall metabolic profile and quality of life. Tumor progression in PCa is strongly driven by androgen receptor (AR) signaling, which is closely linked to cellular metabolic reprogramming, highlighting metabolism as a potential therapeutic target. Aim: The aim of this study was to evaluate and synthesize current evidence on the role of the ketogenic diet (KD) in PCa, with particular emphasis on its interaction with hormonal therapies, underlying metabolic and endocrine mechanisms, and its potential application as an adjunctive strategy in integrated oncologic care. Results: The KD, characterized by high fat and very low carbohydrate intake, induces a metabolic state of ketosis that reduces circulating glucose, insulin, and insulin-like growth factor 1 (IGF-1), potentially counteracting metabolic alterations associated with PCa and its treatments. Preclinical studies consistently demonstrate that carbohydrate restriction and KD can slow tumor growth, modulate key oncogenic pathways such as PI3K/AKT/mTOR, reduce systemic insulin signaling, and enhance survival in prostate cancer models. Additionally, emerging evidence suggests possible synergistic effects when KD is combined with standard therapies, including ADT and immunotherapy. Clinical data, although limited, indicate that low-carbohydrate dietary interventions may improve metabolic parameters and could delay biochemical progression, as suggested by increased prostate-specific antigen (PSA) doubling time. However, results across studies remain heterogeneous, and robust evidence on long-term oncologic outcomes is lacking. Conclusions: Overall, the KD represents a promising but still experimental strategy in PCa management, requiring careful nutritional supervision to avoid adverse effects such as unintended weight loss or sarcopenia. Further well-designed randomized clinical trials are needed to clarify its safety, efficacy, and role in routine clinical practice. Full article

Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN, FOXO, and PIK3CA, are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan–Meier curves were used to assess median overall survival. Cox analysis was performed to generate the adjusted KM curve. Mediation analysis was conducted to determine the relationship between cluster status, TN stage, and survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, cluster 1 (n = 96) and cluster 2 (n = 337). Compared with cluster 2, cluster 1 consisted of decreased expression of PTEN (p < 0.001) and PIK3R1 (p < 0.001), along with increases in the expression of AKT1 (p < 0.001), IRS1/2 (p < 0.001), FASN (p < 0.001), IGFBP2 (p < 0.001), and MTOR (p < 0.001). GSEA analysis revealed changes in lipid metabolism and WNT secretion pathways in cluster 1. Cluster 2 GSEA showed pathway changes related to DNA damage repair and testosterone. Patient characteristics between clusters differed significantly in the T and N stages of tumor but not in other ways. In unadjusted analysis, median overall survival was estimated at 117 months and 232 months for cluster 1 and cluster 2, respectively (p < 0.05). The proportion of patients who went on to develop metastases (p < 0.05) or need chemotherapy (p < 0.05) was increased in cluster 1 compared to cluster 2. Repeat survival analysis adjusted for confounders (T stage, N stage, age at diagnosis, pathologic grade) showed no difference in survival between clusters. Mediation analysis showed that the contribution of cluster status to survival was independent of T or N stage. Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that are consistent with prior studies describing a pattern of insulin dysregulation. Though the group characterized by insulin dysregulation initially showed worse survival outcomes, this difference disappeared when controlling for confounders. Though baseline differences in tumor stage seemed to most readily explain the difference in survival between clusters, mediation analysis showed that the effect of cluster status on survival was independent of tumor stage. This suggests that other confounders, such as pathologic grade or baseline age, may explain the survival difference. Full article

Tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration with tau pathology, are unified by pathogenic tau misfolding, post-translational modification, aggregation, and network-level spread. Yet decades of drug development that predominantly pursued single nodes (e.g., one kinase, one aggregation inhibitor, one monoclonal antibody epitope) have repeatedly delivered late-stage disappointments, underscoring a central lesson: tauopathy behaves less like a linear pathway and more like a coupled system of proteostasis failure, neuroinflammation, synaptic-mitochondrial stress, and metabolic dysregulation. This review examines rhizomes (notably Zingiberaceae genera such as Curcuma, Zingiber, Alpinia, Kaempferia, and Boesenbergia) as chemically diverse “multi-target platforms” whose bioactives can engage several tau-relevant nodes simultaneously. We synthesise evidence across tau phosphorylation (GSK-3β/CDK5 and upstream stress signalling), tau aggregation and seeding, autophagy-lysosome and proteasome pathways, redox-mitochondrial resilience, neuroinflammatory circuits (NF-κB/NLRP3), and neuro-metabolic signalling (insulin-PI3K-AKT, AMPK-mTOR). A translational lens is applied throughout, focusing on drug-likeness and CNS multiparameter optimisation; BBB permeability and efflux; metabolism and bioavailability constraints; and formulation strategies (nanoparticles, phytosomes, engineered exosomes) that may render rhizome-derived scaffolds more clinically plausible. We conclude that rhizomes offer credible mechanistic hypotheses for tau modulation, but progress depends on rigorous standardisation, realistic exposure matching, biomarker-driven study design, and a shift from “single-compound optimism” to network pharmacology with translational discipline. Full article

Colorectal cancer (CRC) is a multifactorial disease arising from dynamic interactions between gut microbiota, inflammatory processes, metabolic reprogramming, and dysregulated host signaling pathways. Increasing evidence highlights the potential of synbiotics—combinations of probiotics and prebiotics—as promising modulators of these processes. This review explores the mechanisms by which synbiotics influence CRC development and progression, integrating data from preclinical and clinical studies. Synbiotics exert beneficial effects by restoring microbial balance, enhancing the production of short-chain fatty acids (SCFAs), strengthening intestinal barrier integrity, and reducing chronic inflammation and oxidative stress. These functional changes converge on key molecular pathways, including Wnt/β-catenin, NF-κB, and PI3K/Akt/mTOR, which regulate tumor cell proliferation, survival, and immune responses. Preclinical studies consistently demonstrate anti-tumor effects, including reduced tumor growth, increased apoptosis, and modulation of the tumor microenvironment. Clinical evidence suggests that synbiotics may improve postoperative outcomes, reduce chemotherapy-related toxicity, and positively influence microbiome composition, although results remain heterogeneous. Emerging approaches focusing on microbiome profiling and personalized synbiotic interventions offer new opportunities for precision medicine in CRC. Overall, synbiotics represent a promising adjunctive strategy in colorectal cancer management, with potential to enhance therapeutic efficacy and improve patient outcomes. Further large-scale clinical studies are needed to validate their long-term benefits and establish standardized treatment protocols. Full article

Background/Objectives: Over the past two decades, non-coding RNAs (ncRNAs) have emerged as key regulators of gene expression, reshaping the classical view of the genome as predominantly protein-coding. Among them, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) play central roles in controlling gene expression at multiple levels. Rather than acting independently, these molecules form complex and interconnected regulatory networks, and their interplay appears particularly relevant in cancer. This review aims to examine the mechanisms underlying miRNA-lncRNA cross-regulation and to explore their functional and clinical implications in tumor biology. Methods: We performed a comprehensive analysis of the current literature focusing on studies investigating miRNA-lncRNA interactions in cancer. Particular attention was given to mechanistic insights, including the competing endogenous RNA (ceRNA) hypothesis, as well as alternative regulatory models involving direct RNA interactions and chromatin-associated processes. Results: miRNA-lncRNA interactions have been associated with cancer progression and therapeutic response across different tumor types, although their mechanisms are highly context-dependent. While the ceRNA hypothesis, based on competition for shared microRNA response elements (MREs), provides a useful framework, it does not fully explain all observed phenomena. Evidence shows that miRNAs can directly regulate lncRNA stability, whereas lncRNAs can influence miRNA biogenesis. Additionally, chromatin-related mechanisms suggest that these interactions extend beyond post-transcriptional regulation. These RNA networks intersect with major oncogenic pathways, including PI3K/AKT/mTOR signaling, hypoxia responses, and epigenetic regulators such as EZH2, thereby affecting key cancer processes such as proliferation, epithelial–mesenchymal transition (EMT), and metabolic reprogramming. From a clinical perspective, the stability of ncRNAs in biological fluids highlights their potential as biomarkers. Combined miRNA-lncRNA signatures may improve diagnostic and prognostic accuracy compared to single markers, although further validation is required. Therapeutic strategies targeting ncRNA networks, such as miRNA mimics, antagomiRs, and lncRNA-directed approaches, are under investigation; however, challenges related to delivery, specificity, and toxicity remain. Conclusions: miRNA-lncRNA cross-regulation represents a complex and multifaceted layer of gene regulation in cancer. A deeper understanding of these interactions could support the development of more accurate diagnostic tools and more effective RNA-based therapeutic strategies, although significant technical and biological challenges still need to be addressed. Full article

Background/Objectives: Capivasertib is a selective pan-AKT inhibitor recently approved in combination with fulvestrant for the treatment of hormone receptor-positive (HR+)/HER2- breast cancer with alterations in the PI3K/AKT pathway. The PI3K/AKT/mTOR signaling cascade represents a critical indication of endocrine resistance and tumor progression in this subtype of breast cancer. The present review summarizes current clinical data regarding the efficacy of capivasertib, either as monotherapy or in combination with other therapeutic agents and discusses emerging biomarkers and mechanisms of resistance. Methods: A literature search of the PubMed database was conducted to identify clinical trials evaluating capivasertib in breast cancer. Studies on capivasertib as monotherapy or in combination with fulvestrant, paclitaxel, or olaparib were included. Results: Findings from phase I–III clinical trials indicate that capivasertib in combination with fulvestrant significantly prolongs progression-free survival in patients with HR+/HER2- advanced breast cancer, particularly in tumors containing PIK3CA, AKT1, or PTEN alterations. Drug combination approaches with paclitaxel or olaparib have demonstrated additive or synergistic effects in triple-negative and DNA repair-deficient contexts, respectively. Monotherapy studies confirm effective pathway inhibition with modest clinical benefit, primarily in AKT1-mutant tumors. Translational analyses suggest that persistent mTORC1-mediated protein synthesis and compensatory signaling activation contribute to acquired resistance. Conclusions: Capivasertib constitutes a clinically validated therapeutic approach for the inhibition of AKT signaling in breast cancer. Its efficacy is most evident when combined with endocrine therapy; however, optimization of patient selection and rational combination strategies remains necessary to overcome resistance associated with mTORC1 activation and signaling redundancy. Full article

Pork production is closely linked to skeletal muscle growth and anabolic processes. This study investigated the effects of dietary supplementation with a multi-strain probiotic (Lactiplantibacillus plantarum, Streptococcus thermophilus, and Bacillus subtilis) on the growth performance, carcass traits, gut microbiota, and potential signaling pathways in growing pigs. A total of 144 weaning piglets (28 days old) were randomly allocated to two groups and fed diets with or without probiotics (0.1%) for 18 weeks. Pigs fed with probiotics showed significantly improved feed efficiency (p < 0.05) and greater muscle mass in the loin eye, arm shoulder, and blade shoulder regions. Microbiome analysis revealed significant enrichment of short-chain fatty acid (SCFA)-producing taxa, including Acidaminococcus, Allisonella, Dialister, and Megasphaera, alongside an increased cecal butyrate level in pigs fed probiotics. Integrated fecal microbiome and serum metabolomics analysis demonstrated that the metabolite profile was substantially altered by the supplementation of probiotics. Additionally, serum insulin levels, expression of the bile acid receptor tgr5, and upstream genes in the PI3K/Akt/mTOR pathway (igf1r, insr, and pi3k) were significantly upregulated (p < 0.05). Collectively, these results suggest that a multi-strain probiotic supplementation may be a promising strategy for improving muscle deposition and feed efficiency in commercial pig production. Full article

Advances in molecular oncology have reshaped the management of breast cancer through the development of pathway-specific targeted therapies. In particular, inhibition of HER2, CDK4/6, and PI3K signaling has yielded substantial clinical benefits in molecularly defined patient populations. This review provides an integrated analysis of three representative agents—trastuzumab, abemaciclib, and alpelisib—highlighting their distinct mechanisms of action, clinical efficacy, and translational relevance in breast cancer, with contextual insights into gynecologic oncology. Evidence from pivotal clinical trials and emerging translational studies demonstrates that trastuzumab remains a cornerstone of HER2-positive breast cancer treatment, while also showing activity in HER2-amplified gynecologic malignancies. Abemaciclib, a selective CDK4/6 inhibitor, has significantly improved outcomes in hormone receptor–positive breast cancer and is being actively explored in tumors characterized by cell cycle dysregulation, including endometrial and ovarian cancers. Alpelisib, targeting the PI3Kα isoform, provides meaningful benefit in PIK3CA-mutated breast cancer and represents a promising strategy in gynecologic tumors with aberrant PI3K/AKT/mTOR pathway activation. Collectively, these agents exemplify precision oncology approaches that align therapeutic strategies with tumor biology. Their integration into biomarker-driven, multimodal treatment frameworks underscores a paradigm shift toward personalized cancer care across breast and gynecologic malignancies. Particular emphasis is placed on the translation of molecular diagnostics into clinical decision-making, including patient selection, resistance mechanisms, and sequencing strategies within evolving precision oncology frameworks. Ongoing clinical and translational research will be critical to refine combination strategies, overcome resistance mechanisms, and identify predictive biomarkers to further optimize patient outcomes. Full article

Autophagy and apoptosis are two evolutionarily conserved catabolic processes that play important roles in maintaining cellular homeostasis and in determining cell fate when cells are exposed to various stresses in vivo. The interaction between autophagy and apoptosis has been studied extensively in cancer research, and it has been shown to affect cancer initiation and tumor formation, disease progression, therapeutic resistance, and overall survival. Autophagy typically functions as a cytoprotective mechanism in cancer cells subjected to metabolic, hypoxic, or therapeutic stress, whereas apoptosis primarily functions as an intrinsic programmed cell death pathway. While apoptosis and autophagy function as distinct pathways, there is significant molecular crosstalk, allowing cells to modulate their behavior from survival to death depending on the severity and duration of exposure to a given stressor and the cellular environment. This review examines the molecular landscape of the autophagy–apoptosis interplay in cancers, with special attention paid to the major signaling pathways involved and their biological outcomes in oncology. We examine the molecular mechanisms and signal transduction pathways involved in the crosstalk between autophagy and apoptosis in cancer. In particular, we focus on several key proteins that regulate this crosstalk, including kinases, caspases, heat shock proteins and transcription factors. Furthermore, we describe the major signal transduction pathways that regulate this crosstalk, including the PI3K/Akt/mTOR, MAPK, unfolded protein response, oxidative stress, and calcium signaling pathways. Additionally, we discussed how dysregulation of these pathways contributes to cancer progression and treatment resistance. Finally, we summarized the use of currently available therapeutic agents targeting the crosstalk between autophagy and apoptosis, including FDA-approved drugs and natural products, with the potential to enhance the effectiveness of anticancer treatments. A better understanding of this complex process will allow the development of new, precision-based, combination cancer therapies. Full article