Ischemic stroke is a leading cause of serious long-term disability and mortality worldwide. Ergothioneine (EGT), a natural dietary sulfur-containing amino acid, possesses potent antioxidant properties. This study investigates the neuroprotective potential of EGT in experimental ischemic stroke and elucidates its underlying molecular signaling pathway. Two ischemic stroke models, the photochemical ischemia model and the middle cerebral artery occlusion (MCAO) model, were established to evaluate the neuroprotective effects of EGT. 2,3,5-Triphenyltetrazolium chloride staining was performed to assess infarct volume, and laser speckle contrast imaging was used to monitor cerebral blood flow. Immunofluorescence was employed to detect the activation of astrocytes and microglia. Proteins involved in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were analyzed by Western blot to explore the underlying mechanism of EGT. In both photochemical ischemia and middle cerebral artery occlusion models, EGT significantly reduced infarct volume, improved cerebral perfusion and attenuated glial cells activation. Mechanistically, EGT promoted PI3K/Akt phosphorylation, reduced cytoplasmic Kelch-like erythroid cell-derived homology-associated protein 1 expression, and enhanced nuclear Nrf2 translocation. Notably, PI3K inhibitor, LY294002, completely abolished the neuroprotective effects of EGT. EGT exhibits significant neuroprotection against experimental ischemic stroke by mitigating oxidative stress and neuroinflammation, and its efficacy is critically dependent on the activation of the PI3K/Akt/Nrf2 signaling pathway.

Discovery of novel bis-aryl urea-linked triazine derivatives as dual PI3K/mTOR inhibitors via scaffold hopping strategy and biological activity evaluations.

Aberrant phosphatidylinositol 3-kinase (PI3K) activation drives many cancers, but PI3K inhibitors like Pictilisib often induce cytostasis rather than cytotoxicity, limiting their therapeutic potential. Here we demonstrate that PI3K inhibition combined with nutrient stress triggers methuosis, a non-apoptotic form of programmed cell death characterized by dysregulated macropinosomes. This response occurs selectively in PI3K-aberrant cancer cells that maintain macropinocytic uptake despite PI3K inhibition. Methuosis-associated vacuoles originate from macropinosomes that retain endosomal markers but fail to undergo lysosomal fusion. Active macropinocytic uptake is essential for methuosis, as demonstrated by suppression with EIPA and Bafilomycin A1, whereas the AKT inhibitor MK2206 has no effect, establishing that direct PI3K inhibition, rather than AKT signaling, is required. Mechanistically, PI3K blockade prevents conversion of phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) to phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P3) causing PI(4,5)P2 to accumulate on internalizing macropinosomal membranes. This aberrant PI(4,5)P2 enrichment impairs ion channel function across multiple channel families, disrupting intracellular osmotic balance. Ion dysregulation triggers aquaporin-1-mediated water influx, driving catastrophic vacuolar expansion and cell death. Although Pictilisib activates pro-survival autophagy, this fails to prevent methuosis-mediated cytotoxicity. In xenograft models, dietary restriction synergizes with Pictilisib to suppress tumor growth, correlating with pronounced intratumoral vacuolization. These findings reveal that combining PI3K inhibition with nutrient restriction converts cytostatic responses into methuosis-driven cytotoxicity via PI(4,5)P2-dependent macropinocytic dysregulation, providing a rational pharmacologic-dietary strategy to enhance PI3K-targeted cancer efficacy.

The structural design of bone scaffolds determines the local fluid mechanical microenvironment; however, how such cues program stem cell metabolism to drive osteogenesis remains unclear. In this study, Voronoi-based trabecular-like scaffolds with tunable porosity were engineered to modulate fluid shear stress (FSS) while preserving a consistent topology. Computational fluid dynamics analyses confirmed that architectures with lower porosity generated higher FSS, enabling controlled investigation of mechano-metabolic coupling. Under dynamic culture conditions, bone marrow mesenchymal stem cells (BMSCs) cultured on high-FSS scaffolds exhibited enhanced osteogenic differentiation in vitro and promoted bone regeneration in vivo. Integrated transcriptomic, proteomic, and metabolomic analyses identified caveolin-1 (CAV1) as a prominent FSS-responsive membrane regulator. Mechanistically, CAV1 enhanced phosphatidylinositol 3-kinase (PI3K)–AKT signaling, stabilized hypoxia-inducible factor-1α (HIF-1α), and induced a glycolytic shift that supports the energetic and biosynthetic demands of osteogenesis. Pharmacological inhibition of PI3K, HIF-1α, or glycolysis abolished FSS-driven osteogenic responses, validating a CAV1-centered mechano-metabolic axis. These findings establish a direct link between scaffold microarchitecture and metabolic regulation of osteogenesis and provide design principles for mechanically instructive bone repair materials.

Premature ovarian failure (POF) affects 1-5% of women under 40 years old and is characterized by granulosa cells (GCs) apoptosis and follicular atresia. However, the pathogenesis of POF is complex and lacks effective prevention and treatment strategies. N-carbamylglutamate (NCG), a bioactive substance known for its antioxidant properties; however, whether it can alleviate POF remains unclear. This study using the cyclophosphamide (Cy)-induced POF mouse model, and demonstrated that NCG, has beneficial effects in alleviating POF symptoms and restoring the intestinal mucosal barrier through gut microbiota-metabolite crosstalk. Integrated 16S rRNA sequencing, untargeted metabolomics, and fecal bacteria transplantation (FMT) experiments revealed that NCG induced restructuring of gut microbial communities, with enrichment of Muribaculum intestinale and concomitant elevation of its associated Tryptophan-derived metabolite, Tryptophanol. Mechanistically, Tryptophanol, supplementation alleviated POF by reducing mouse GCs apoptosis and oxidative stress via inhibiting Phosphatidylinositol 3-kinase/ Protein Kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways, thereby restoring ovarian function and fertility, and the efficacy of NCG in alleviating POF relies on promoting Tryptophanol-mediated anti-oxidative stress. Our findings, highlight the "gut microbiota-Tryptophanol-ovary" axis in POF pathogenesis, and propose a potential therapy for NCG to regulate gut microbiota to restore ovarian redox homeostasis to alleviate POF.

Targeting BCL-2 and PI3K signaling pathways enhances cytotoxicity of gemtuzumab ozogamicin against acute myeloid leukemia cells.

The intensification of radiotherapy is an effective way to improve the therapeutic efficacy of radiation-sensitive malignancies such as esophageal cancer (EC). Esophageal squamous cell carcinoma (ESCC) accounts for 85% of all EC cases worldwide, with a relatively higher incidence and mortality in East Asia. In this study, we explored the functions and mechanisms of programmed cell death 10 (PDCD10) in the malignancy and radiotherapy sensitivity of ESCC cells. We observed that PDCD10 is highly expressed in ESCC tissues and is correlated with a poor prognosis in patients with ESCC. PDCD10 downregulation suppressed ESCC cell proliferation, migration, and invasion but promoted apoptosis. In addition, it enhanced ionizing radiation (IR)-induced ESCC cell damage, whereas PDCD10 overexpression had the opposite effect. Mechanistically, PDCD10 increased the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in ESCC cell lines. The administration of LY294002, a PI3K inhibitor, significantly inhibited the oncogenic functions of PDCD10, leading to an increase in IR-induced cell damage. These findings establish PDCD10 as a critical intrinsic regulator of the sensitivity of ESCC cells to IR through the modulation of the PI3K/AKT pathway.

Metastasis is the leading cause of mortality in bladder cancer (BC). This study investigates the antimetastatic potential of ZSTK474, a phosphatidylinositol 3-kinase (PI3K) inhibitor developed for solid tumor therapy. Specifically, the study evaluates the effects of ZSTK474 on tumor cell migration and invasion, two critical processes in metastasis using in vitro assays. Human BC cell lines, CAL29 and BIU87, were treated with ZSTK474 at concentrations of 0, 0.05, 0.25, and 1.5µM. Cell proliferation was assessed using the BrdU incorporation assay. Migration capacity was evaluated through scratch and Transwell migration assays, while invasion potential was determined using a Matrigel-coated Transwell invasion assay. Western blotting was performed to analyze the expression levels of Girdin, phosphorylated Girdin (p-Girdin), phosphorylated Akt (p-Akt), and PI3K. Treatment with ZSTK474 significantly inhibited BC cell proliferation, as demonstrated by the BrdU incorporation assay. Additionally, a substantial reduction in cell invasion was observed in the Transwell invasion assay (p < 0.01). Western blot analysis revealed that ZSTK474 suppressed the phosphorylation of Girdin in BC cells. Higher concentrations of ZSTK474 were associated with decreased relative expression levels of Girdin, p-Girdin, p-Akt, and PI3K. However, no significant inhibitory effect on Akt expression was detected following ZSTK474 treatment. Although total Akt protein levels remained unchanged, whereas phosphorylated Akt (p-Akt) was significantly reduced. The findings of this study suggest that ZSTK474 effectively inhibits bladder cancer cell migration and invasion by suppressing key signaling pathways involved in metastasis. Specifically, ZSTK474 reduces the phosphorylation of Girdin, an Akt substrate implicated in tumor migration and invasion. These results provide further evidence supporting the therapeutic potential of ZSTK474 in mitigating metastatic progression in bladder cancer.

Uveal melanoma (UM) was prone to metastasis and had an extremely poor prognosis. High-mobility group protein A1 (HMGA1) was known to promote proliferation and invasion in various tumors, but its molecular mechanism in UM remained unclear. The effect of HMGA1 on the proliferation, migration, and invasion of UM cells was investigated, and whether it functioned through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/matrix metalloproteinase-9 (MMP-9) pathway was explored. HMGA1 overexpression (OE) and knockdown (KD) models were established in two UM cell lines (C918, MUM-2B). Cell functions were assessed using MTT assay, EdU (5‑ethynyl‑2'‑deoxyuridine) incorporation assay, scratch wound healing assay, and Matrigel-Transwell assay. The expression of PI3K, phosphorylated PI3K (p-PI3K), Akt, phosphorylated Akt (p-Akt), and MMP-9 was detected by Western blot (WB). Pathway intervention was performed using the PI3K inhibitor LY294002. Compared with the control group, HMGA1 overexpression significantly up-regulated the proliferation, migration, and invasion abilities of both cell lines, and led to a fold-dependent up-regulation of PI3K/Akt pathway activation and MMP-9 expression. In contrast, HMGA1 knockdown significantly down-regulated the above indicators. After treatment with LY294002, the tumor-promoting effects induced by HMGA1 overexpression were significantly reversed. HMGA1 significantly promoted the proliferation, migration, and invasion of UM cells from different origins (primary C918, metastatic MUM-2B) by activating the PI3K/Akt pathway and upregulating MMP-9 expression, suggesting its potential as a target for molecular targeted therapy in UM.

BackgroundThe Na+/H+ exchanger isoform 1 (NHE1) inhibitor is an effective agent applied to prevent doxorubicin (Dox) induced cardiotoxicity (DIC). This research investigated the protective effect of N-(4-guanidinobutyl)-4-hydroxy-3-methoxybenzamide (GBVAM), a novel NHE1 inhibitor synthesized by our lab on the DIC model.MethodsWe established the DIC mice by Dox intraperitoneal injection (16 mg/kg) for 21 days and divided the mice into Dox, Dox+GBVAM (5 mg/kg/day or 10 mg/kg/day) and Dox+GBVAM (5 mg/kg/day)+LiCl (2 mg/kg/day) groups. The H9c2 cells were divided into control, Dox (2 μM), Dox (2 μM)+GBVAM (1 μM or 10 μM), Dox (2 μM)+GBVAM (1 μM)+LiCl (5 mM), and Dox (2 μM)+GBVAM (1 μM)+LY294002 (10 μM) groups. We applied LiCl and LY294002 as NHE1 activator and phosphatidylinositol 3-kinase (PI3K) inhibitor to estimate the effect of NHE1 and PI3K pathway in the protection of GBVAM. In vivo, we examined the myocardial enzymes, cardiac function and oxidative stress indicators. In vitro, we also investigated the cardiomyocytes apoptosis and autophagy indicators as well as the PI3K/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways.ResultsOur results indicated that GBVAM played the protective effect on DIC in vivo by reversal on the myocardial enzymes, cardiac function and oxidative stress. The transcriptomic analysis data indicated that the differentially expressed genes (DEGs) associated with the protective effect of GBVAM included autophagy, mTOR and p53. Moreover, GBVAM also had an inhibition on the cardiomyocytes apoptosis and autophagy caused by Dox, which were all attenuated by LiCl treatment in vivo. The vitro experiment showed that GBVAM alleviated the oxidative stress, apoptosis and autophagy via inhibition of NHE1 and PI3K/Akt/mTOR signaling pathways. In addition, the inhibition of PI3K/Akt/mTOR signaling pathways caused by DOX could be activated by GBVAM, which were attenuated by LiCl addition.ConclusionOur results indicated that GBVAM inhibited apoptosis and autophagy in DIC model by NHE1 inhibition, which might be via PI3K/Akt/mTOR signaling pathway.

Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer‐related mortality among women worldwide. Triple‐negative breast cancer (TNBC) poses a major clinical challenge due to its aggressive nature, limited therapeutic options, and high propensity for drug resistance. Dysregulation of the phosphatidylinositol 3‐kinase (PI3K)/AKT/mTOR and histone deacetylase (HDAC) signaling pathways has been implicated in TNBC progression and therapeutic resistance, highlighting their potential as combinatorial targets. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazine‐based multitarget inhibitors aimed at the dual inhibition of PI3K and HDAC. Among the synthesized compounds, 5b and 5f demonstrated the most promising profiles, exhibiting low nanomolar IC50 values against HDAC6 (2.33 and 6.02 nM) and PI3Kα (17.5 and 236 nM), respectively. Both compounds reduced cell viability in breast cancer cell lines, with IC50 values below 5 µM in MDA‐MB‐231 cells. Western blot analysis confirmed inhibition of HDAC and PI3K signaling in treated cells. Molecular docking and dynamics simulations further revealed stable binding modes and favorable interactions within the active sites of both targets. Overall, 5b and 5f represent promising lead candidates for further optimization toward the development of novel dual HDAC/PI3K inhibitors with potential application in TNBC therapy, as evaluated in TNBC‐relevant models.

Peripheral T-cell lymphomas (PTCLs) are rare, heterogeneous, aggressive lymphomas. Five-year overall survival (OS) remains approximately 30%-40%, and most patients will develop relapsed or refractory (R/R) disease. Duvelisib is an oral dual inhibitor of phosphatidylinositol 3-kinase (PI3K)-δ and PI3K-γ isoforms. Here, we report on the final analysis of the phase II PRIMO trial (ClinicalTrials.gov identifier: NCT03372057; Secura Bio, Inc) evaluating duvelisib monotherapy in R/R PTCL. PRIMO was conducted in two phases (dose optimization and dose expansion [PRIMO-EP]) at 45 centers globally. Eligible patients were age 18 years and older, had histologically confirmed diagnosis of PTCL, and had received ≥2 cycles of one standard regimen for PTCL. Based on dose optimization results, the selected regimen for PRIMO-EP was 75 mg twice a day for two cycles (to maximize disease control) followed by 25 mg twice a day (to reduce late toxicities), continued until progressive disease or unacceptable toxicity. PRIMO-EP (N = 123) outcomes included independent review committee-assessed objective response rate (ORR): 48.0%, complete response rate (CRR): 33.3%, median progression-free survival (mPFS): 3.4 months, median OS (mOS): 12.4 months, and median duration of response (mDOR): 7.9 months. In the angioimmunoblastic T-cell lymphoma (AITL) subgroup, outcomes were ORR: 62.2%, CRR: 51.4%, mPFS: 8.3 months, mOS: 18.1 months, and mDOR: 11.3 months. Treatment-emergent adverse events (TEAEs; any grade) occurred in 120 patients (97.6%), and TEAEs grade ≥3 occurred in 91 patients (74.0%). TEAEs resulting in dose hold or dose reduction occurred in 44.7% and 9.8% of patients, respectively. The PRIMO study demonstrates significant activity and tolerability of duvelisib in patients with R/R PTCL, most notably in the AITL subgroup. This provides strong rationale for further development in PTCL, and more specifically in the subgroup of nodal T-follicular helper cell lymphoma.

Objective: To explore the regulatory effect of the phosphatidylinositol 3-kinase (PI3K) /protein kinase B (AKT) /hypoxia-inducible factor 1α (HIF-1α) glycolysis signaling pathway on urinary metabolites during the progression of silicosis fibrosis and its related metabolic pathway mechanisms. Methods: From March to June 2023, 36 SPF-grade C57BL/6 mice were randomly divided into the control group, the silica (SiO(2)) model group, the PI3K inhibitor LY294002 early/late intervention group, and the HIF-1α inhibitor 2-methoxyestradiol (2-ME2) early/late intervention group, totaling 6 groups, with 6 mice in each group. The silicosis mice model was established by tracheal instillation 50 μl of 200 mg/ml SiO(2) suspension. Corresponding intervention agents were intraperitoneally injected on the 2nd day (early stage) and on the 29th day (late stage) after dust exposure, and the intervention was carried out continuously for 55 d and 28 d respectively. On the 56th day of the experiment, the mice were sacrificed and the lung tissues were subjected to pathological examination. Non-targeted metabolomics analysis of urine was conducted using ultra-performance liquid chromatography-tandem mass spectrometry. Principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to screen out the differential metabolites, and metabolic pathway enrichment analysis was performed. Results: Mice in the SiO(2) model group exhibited dull fur coloration, reduced activity, diffuse pulmonary fibrosis, alveolar structural damage, and extensive inflammatory cell infiltration after dust exposure. All intervention groups showed significantly improved general condition compared to the SiO(2) model group, with markedly reduced pulmonary fibrosis severity. Early intervention groups demonstrated superior pathological improvement outcomes compared to the late intervention groups. Metabolomics analysis revealed that PCA and OPLS-DA of urine samples demonstrated significant differences in metabolic profiles between the control group and SiO(2) model group. A total of 13 differential metabolites were identified, involving two core metabolic pathways: sphingolipid metabolism and riboflavin metabolism. All intervention groups exhibited a trend of metabolic profiling regression toward the control group, with 5-10 differential metabolites screened out, capable of reversing 2-4 core abnormal metabolite levels. Post-intervention differential metabolites were primarily enriched in four metabolic pathways: sphingolipid metabolism, riboflavin metabolism, unsaturated fatty acid biosynthesis, and linoleic acid metabolism (P<0.05) . Conclusion: This study demonstrates that silicosis development is closely associated with dysregulation of sphingolipid and riboflavin metabolic pathways. Targeted interventions can mitigate pulmonary fibrosis damage by restoring core metabolite levels. The PI3K/Akt/HIF-1α signaling pathway may serve as a key mechanism regulating these metabolic abnormalities, providing an experimental foundation for early intervention and metabolic biomarker screening in pneumoconiosis.

Treatment and survival outcomes for patients with follicular lymphoma and POD24: a systematic review and meta-analysis.

Phosphatidylinositol 3-kinase (PI3K) (EC2.7.1.137) is an enzyme essential for a variety of biological processes, including inflammation and neuroplasticity. There is a close, positive relationship between these biological functions and the action of psychostimulant drugs such as cocaine and methamphetamine (METH). This suggests that the inhibition of PI3K might regulate METH-induced behavior such as hyperlocomotion and stereotyped behavior. To evaluate the effects of PI3K inhibition on METH-induced behavior, mice were treated with wortmannin, a potent PI3K inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. In addition, additional experiments were conducted to examine the effects of wortmannin on other aspects of behavior. Pretreatment of mice with wortmannin (3 and 10 mg/kg) significantly inhibited METH (10 mg/kg)-induced stereotyped behavior in a dose-dependent fashion. Stereotyped biting was most robustly reduced by wortmannin, ameliorating the frequency of total stereotypy. Wortmannin (10 but not 3 mg/kg) had a significant inhibitory effect on METH (3 mg/kg)-induced hyperlocomotion. Wortmannin had no effect on other aspects of behavior relevant to emotion or memory. In conclusion, non-glycogen synthase kinase-3β (GSK3β) mediated PI3K signaling pathways appear to contribute to the expression of acute METH effects on locomotion and stereotyped behavior in a manner that is different from PI3K-GSK3β mediated signaling.

Hydroalcoholic gel of Angelica sinensis polysaccharides promotes wound healing by suppressing ferroptosis through PI3K/AKT/Nrf2 signaling pathway.

Genomic determinants of response to alpelisib plus fulvestrant in the SOLAR-1 trial.

Clinical trials have demonstrated that venlafaxine affects brain functions in healthy subjects, but its underlying mechanisms remain unclear. The objective of this study was to systematically evaluate the effects of venlafaxine on the expression and activity of catechol-O-methyltransferase (COMT) in cortex of nondepressed rats and mice. Chronic in vivo exposure to venlafaxine for 8 days led to increases in cerebral COMT expression and activity, decreases in the methyl donor S-adenosylmethionine (SAM) levels, downregulation of H3K4me3 and H3K27me3 expression, and alterations in locomotor and exploration activities. Data from U251 cells and primary astrocytes showed that venlafaxine significantly upregulated COMT, p-AKT, p-P70S6K, and p-4EBP1 expression and decreased cellular SAM levels. Phosphatidylinositol 3-kinase inhibitor LY294002, mammalian target of rapamycin inhibitor rapamycin, silencing P70S6K, or silencing 4EBP1 remarkably attenuated venlafaxine-induced upregulation of COMT. Rapamycin or silencing P70S6K and 4EBP1 reversed venlafaxine-mediated deficiency of cellular SAM levels. In mice, rapamycin significantly attenuated venlafaxine-induced increases in cortical expression of COMT, p-P70S6K, and p-4EBP1, decreases in cortical SAM levels and locomotor and exploration activities, and downregulations of H3K4me3 and H3K27me3 expression. Furthermore, COMT inhibitor tolcapone reversed venlafaxine-induced decreases in SAM levels, H3K4me3 and H3K27me3 expression, and locomotor and exploration activities. Supplementing SAM also remarkably attenuated venlafaxine-induced decreases in H3K4me3 and H3K27me3 expression and behavioral alterations. These observations were further confirmed in U251 cells and primary astrocytes. These results indicate that venlafaxine induces cortical COMT via phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway to decreasing SAM levels. Depletion of cortical SAM levels partly contributes to the decreases in activities of locomotor and exploration and expression of H3K4me3 and H3K27me3. SIGNIFICANCE STATEMENT: This study revealed that venlafaxine upregulated cortical catechol-O-methyltransferase expression and activity via activating phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway. The induction of catechol-O-methyltransferase led to depletion of cortical S-adenosylmethionine, which may partly contribute to the decreases in locomotor and exploration activities and downregulations of H3K4me3 and H3K27me3 expression in cortex of rats and mice.

Breast cancer is the most common malignancy in women and a major cause of cancer-related mortality. While early-stage disease is often curable, many patients ultimately develop distant metastases, with the brain representing one of the most devastating sites. Breast cancer brain metastasis (BCBM) is particularly prevalent in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes, leading to severe neurological symptoms, diminished quality of life, and poor prognosis. Despite progress in systemic therapy for primary tumors, outcomes for patients with BCBM remain poor, and these patients are frequently excluded from clinical trials. The pathogenesis of BCBM involves complex interactions between tumor cells and the central nervous system microenvironment. Crossing the blood-brain barrier and adapting to the brain niche requires tumor-stroma crosstalk, including signaling with astrocytes and microglia, which promotes immune evasion, therapeutic resistance, and metastatic outgrowth. Although advances in preclinical models and molecular profiling have provided valuable insights, critical mechanisms remain incompletely understood. Systemic therapies are increasingly important, with HER2-targeted agents, tyrosine kinase inhibitors, and subtype-specific regimens showing activity. Novel approaches, including poly (ADP-ribose) polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase inhibitors, and antibody-drug conjugates, are under evaluation. This review synthesizes epidemiology, molecular mechanisms, and emerging therapies of BCBM, underscoring advances achieved and highlighting the urgent need for novel targeted strategies and inclusive clinical trials.

Chronic oxidative stress is recognized as a hallmark of cancer and represents a potentially targetable vulnerability in malignant cells. Oncogenic mutations in phosphatidylinositol 3-kinase (PI3K) are frequently observed across diverse malignancies, playing a crucial role in cancer progression. However, the relationship between PI3K–AKT signaling, mitochondrial fitness, and ferroptosis resistance remains poorly understood. We compared the sensitivity of MCF-7 cells (harboring oncogenic PI3K activation) and MDA-MB-231 cells with oxidative stress and ferroptosis inducers using high-content imaging analysis and flow cytometry. RNA-sequencing was performed to identify transcriptomic changes following PI3K inhibition. Mitochondrial fitness was assessed by measuring mitochondrial mass, membrane potential, ATP production, and glutathione levels. Functional validation was conducted through pharmacological manipulation using PI3K–AKT–mTOR pathway inhibitors and AKT activators, as well as genetic approaches involving ectopic expression of oncogenic PIK3CA-E542K in HeLa cells. Cancer cells with constitutive PI3K activation exhibited high resistance to oxidative stress and ferroptosis compared with cells without oncogenic PI3K mutations. Mechanistically, PI3K–AKT signaling orchestrated an augmented mitochondrial gene program, enhancing mitochondrial fitness and antioxidant capacity. Inhibition of the PI3K–AKT–mTOR pathway selectively increased reactive oxygen species levels, compromised mitochondrial fitness, induced mitophagy, and sensitized cells with oncogenic PI3K activation to ferroptosis. Conversely, ectopic expression of oncogenic PIK3CA or pharmacological activation of AKT conferred resistance to oxidative stress and ferroptosis in a mitochondria-dependent manner, as evidenced by the abrogation of protective effects upon mitochondrial uncoupling. Our findings establish a novel link between enhanced mitochondrial fitness and ferroptosis resistance in cancer cells with hyperactive PI3K signaling. These results suggest that combining ferroptosis induction with PI3K inhibition and mitochondrial fitness impairment may offer a promising therapeutic strategy for cancers harboring oncogenic PI3K mutations. This approach provides new insights into potential treatment modalities that exploit the interplay between oncogenic signaling pathways and cellular redox homeostasis in cancer cells.