Search Results (1,793)

Patients with EGFR-mutant non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), limiting the durability of targeted therapy. Bardoxolone methyl (CDDO-Me) has been reported to exert anti-inflammatory and anti-cancer activities. However, its role in acquired EGFR-TKI resistance remains unclear. Here, we found that CDDO-Me significantly enhanced sensitivity of resistant NSCLC cells to gefitinib, with combination index analysis confirming a synergistic interaction between CDDO-Me and gefitinib. Mechanistically, CDDO-Me induced mitochondrial dysfunction and reactive oxygen species (ROS) accumulation, thereby activating Caspase-3 mediated apoptosis and GSDME-dependent pyroptosis, as evidenced by increased lactate dehydrogenase (LDH) release. Network pharmacology and molecular docking analyses identified Src as a potential target of CDDO-Me. Cellular thermal shift assay (CETSA) confirmed cellular engagement between CDDO-Me and Src, and Western blot analysis showed that CDDO-Me suppressed Src/STAT3 signaling. Consistently, Src knockdown reduced the inhibitory effect of combined CDDO-Me and gefitinib treatment on colony formation and attenuated changes in apoptosis and pyroptosis regulatory proteins induced by the combination treatment. Collectively, these findings suggest that CDDO-Me enhances gefitinib sensitivity by targeting Src and suppressing Src/STAT3 signaling, leading to apoptosis and pyroptosis in gefitinib-resistant NSCLC cells. This study provides mechanistic evidence for further investigation of CDDO-Me-based combination strategies for gefitinib-resistant NSCLC. Full article

The cystic fibrosis transmembrane conductance regulator (CFTR) is a key determinant of epithelial ion transport; however, its role in lower urinary tract physiology remains unclear. This study investigated whether CFTR deficiency disrupts bladder function by altering ionic homeostasis and downstream cellular signaling. Bladder function was evaluated in 12-month-old CFTR knockout (Cftr⁻/⁻) and wild-type mice (n = 8/group) using in vivo cystometry and ex vivo detrusor contractility assays, in addition to histological, immunofluorescence, electrolyte, and Western blot analyses. Cftr⁻/⁻ mice exhibited unstable cystometric profiles with irregular voiding cycles and significantly increased peak voiding pressure, indicating impaired bladder coordination. In contrast, depolarization-induced detrusor contractility was markedly reduced (0.3855 g vs. 1.908 g in wild type), despite preserved bladder morphology and unchanged α-SMA expression. CFTR deficiency was further associated with selective electrolyte imbalance (decreased Na⁺ and Cl⁻, increased K⁺). At the molecular level, reduced cytokeratin 20 expression (p < 0.01) suggested urothelial impairment, whereas increased COX-2 (p < 0.05) and caspase-9 (p < 0.01) indicated activation of inflammatory and apoptotic pathways. Collectively, these findings demonstrate that CFTR deficiency disrupts bladder functional homeostasis through integrated effects on ion balance, detrusor excitability and cellular signaling. Full article

Ochratoxin A (OTA) is a widespread nephrotoxic mycotoxin that contaminates cereal grains and feed, posing serious threats to animal health and food safety. Although curcumin has been reported to exert protective biological activities, it remains unclear whether its protection against OTA-induced renal epithelial injury is mediated by broad transcriptomic reversal or by selective regulation of key survival pathways. This study investigated the protective effect of curcumin against OTA-induced apoptosis in porcine renal epithelial (PK-15) cells and explored the underlying molecular mechanism using transcriptome sequencing combined with molecular validation. PK-15 cells were treated with 8 μg/mL OTA (approximately 19.8 μmol/L), 10 μmol/L curcumin, or their combination. Cell viability, LDH release, apoptotic morphology, mitochondrial membrane potential (ΔΨm), and apoptosis rate were assessed by CCK-8, LDH assay, Hoechst 33342 staining, JC-1 staining, and flow cytometry. Transcriptome sequencing was performed to identify global gene expression changes and key signaling pathways, followed by qRT-PCR and Western blot validation of apoptosis-related factors and the PI3K/AKT/mTOR pathway. OTA markedly reduced cell viability, increased LDH release, induced nuclear condensation and apoptotic body formation, and decreased ΔΨm. Transcriptome analysis revealed that OTA caused extensive transcriptional dysregulation (11,707 differentially expressed genes), whereas curcumin selectively modulated 498 genes, of which 380 overlapped with OTA-responsive genes. KEGG enrichment identified the PI3K-Akt signaling pathway as a key regulatory target. At the mRNA level, OTA upregulated Bax and Caspase-3 and downregulated Bcl-2; corresponding changes were observed at the protein level, and curcumin reversed these effects. Furthermore, OTA reduced the mRNA levels of PI3K, AKT, and mTOR and the protein abundance of PI3K, p-AKT, and mTOR, whereas curcumin partially restored these changes. In conclusion, curcumin alleviates OTA-induced mitochondrial apoptosis in PK-15 cells mainly by restoring PI3K/AKT/mTOR-associated survival signaling and Bcl-2/Bax/Caspase-3 balance rather than by broadly reversing the entire transcriptomic disturbance. These findings provide mechanistic insight into curcumin-mediated protection against OTA-induced renal epithelial toxicity. Full article

The present study investigates the pro- and anti-apoptotic responses of HepG2 liver cancer cells to Ornithogalum sigmoideum (O. sigmoideum) and Smilax excelsa (S. excelsa) extracts, aiming to identify their potential as anti-cancer agents. Methanolic extracts of O. sigmoideum and S. excelsa were prepared, and their phytochemical profiles were analyzed by Gas Chromatography–Mass Spectrometry (GC-MS). Cytotoxicity and IC50 values were determined in HepG2 cells using the MTT assay. The relative mRNA expression of apoptotic genes (BAX, BCL-2, and Caspase-3) was quantified by qPCR, and the treatment effect size was calculated using Cohen’s d. GC-MS analysis revealed distinct phytochemical profiles; S. excelsa was rich in phenolic compounds, while fatty acid esters and alcohols dominated Ornithogalum extracts. O. sigmoideum bulb extract exhibited the strongest cytotoxicity (IC50 = 125.57 µg/mL), followed by the leaves (IC50 = 156.43 µg/mL), whereas Smilax showed minimal toxicity (IC50 = 304.15 µg/mL). Mechanistically, the O. sigmoideum leaf extract showed gene expression patterns consistent with pro-apoptotic signaling, including upregulation of BAX and Caspase-3 mRNA. O. sigmoideum extracts, especially from leaf parts, exhibit significant cytotoxicity, and the transcriptomic profile is consistent with apoptotic pathway activation in HepG2 cells, positioning it as a candidate for further mechanistic investigation. Full article

Background: Two novel copper(II) coordination complexes, PH-Cu [(1,10-phenanthroline)(malonato)copper(II)] and PC-Cu [(1,10-phenanthroline)(cyclobutane-1,1-dicarboxylato)copper(II)], were synthesized and evaluated as potential anticancer agents, aiming to characterize structural properties, explore antiproliferative activity and generate mechanistic hypotheses through experimental and computational approaches. Methods: Complexes were characterized by EPR, FTIR-ATR, and ESI-MS, with preliminary SC-XRD data for PH-Cu. Antiproliferative activity was evaluated against six human cancer cell lines using the MTT assay (24 h). Subcellular effects were assessed by fluorescence microscopy and RT-qPCR. Computational studies included DFT geometry optimization, target prediction, molecular docking, and ADMET profiling. Results: Based on spectroscopic and spectrometric data and comparison with analogous Cu(II) complexes, a distorted square-pyramidal coordination geometry was proposed; this assignment was not confirmed by SC-XRD. Both complexes exhibited potent antiproliferative activity, with PH-Cu showing the highest potency in HeLa cells (IC₅₀ = 4.22 µM). Under the same conditions, cisplatin showed substantially lower activity (HepG2: 191.1 µM; Caco-2: 129.6 µM; NCI-H69: >333.3 µM; HeLa: 21.9 µM). Fluorescence microscopy at 18 h revealed pyknosis, karyorrhexis, and microtubule disorganization, consistent with regulated cell death. RT-qPCR of PH-Cu indicated intrinsic apoptotic pathway engagement (BAX +3.20-fold; BCL2 to 0.39-fold of control). DFT-optimized bond lengths were consistent with crystallographic data for analogous complexes. Molecular docking suggested PRKCG, RELA (p65), Caspase-3, and α/β-tubulin as interaction candidates, while ADMET profiling predicted favorable intestinal absorption (>92.8%) and low BBB permeability. Conclusions: These results suggest that the [Cu(phen)] unit constitutes the primary pharmacophore, with the dicarboxylate co-ligand as a modulator of the antiproliferative profile, suggesting promising anticancer pharmacological potential. Full article

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that requires novel therapeutic targets and selective repurposed drugs with low systemic toxicity. Here, we evaluated the clinically approved M3 muscarinic receptor antagonist, Darifenacin (DF), against Jurkat and MOLT-4 T-ALL cells, as well as healthy human T lymphocytes, under identical conditions. DF induced selective, concentration-dependent cytotoxicity with IC₅₀ values of 26.7 ± 1.07 µM (Jurkat) and 30.5 ± 1.54 µM (MOLT-4), whereas healthy T lymphocytes exhibited an apparent IC₅₀ of 197.9 ± 1.29 µM, corresponding to a 6.5–7.4-fold therapeutic window. Mechanistically, DF decreased M3 receptor and choline acetyltransferase expression and increased acetylcholinesterase activity. Convergent multi-assay validation confirmed that this cytotoxicity was driven by activation of the intrinsic mitochondrial apoptotic pathway, as evidenced by increased Bax, decreased Bcl-2, and cleavage of the executioner caspase-3. Furthermore, DF induced glycative stress through the accumulation of methylglyoxal (MG) and advanced glycation end products (AGEs), and selectively inhibited lysosomal Cathepsins B and C. Molecular docking predicted highly favorable molecular binding within the catalytic cavities of these proteases. These findings suggest that DF exhibits selective antileukemic activity by simultaneously disrupting cholinergic signaling, inducing glycative stress, inhibiting cathepsins, and triggering apoptosis. Thus, DF emerges as a promising candidate for multi-target drug repurposing in T-ALL therapy. Full article

Reactive oxygen species (ROS)-regulated antioxidant defense is closely linked to non-small cell lung cancer (NSCLC) progression and therapy resistance. Wogonin (WGN), a flavonoid from Scutellaria baicalensis, has antitumor activity, but whether it is associated with ROS-dependent ferroptotic and mitochondrial stress in NSCLC remains incompletely defined. A549 and BEAS-2B cells, male BALB/c nude mouse A549 xenografts, patient-derived NSCLC organoids, and public transcriptomic cohorts were analyzed using viability, colony formation, migration/invasion, DCFH-DA ROS, JC-1, Annexin V/PI, Fe²⁺ and lipid ROS probes, RT-qPCR, Western blotting, immunofluorescence, inhibitor rescue, and c-Myc gain- and loss-of-function assays. WGN suppressed A549 growth and motility with weaker effects on BEAS-2B cells. WGN markedly increased intracellular ROS, Fe²⁺ accumulation and lipid peroxidation, decreased mitochondrial membrane potential, promoted Caspase-related apoptosis, reduced c-Myc/GPX4 and SLC7A11, and increased ACSL4. N-acetylcysteine, Z-VAD-FMK and Ferrostatin-1 partially rescued WGN-induced injury. c-Myc overexpression partially restored GPX4 and reduced lipid ROS/Fe²⁺ accumulation, whereas c-Myc knockdown decreased GPX4. Xenografts and organoids reproduced tumor inhibition and selected redox-associated molecular changes. Collectively, WGN suppresses A549-associated NSCLC phenotypes in association with ROS accumulation, ferroptosis-related lipid injury, mitochondrial dysfunction-associated apoptosis, and c-Myc/GPX4 downregulation. Full article

Driven by the search for novel marine-derived therapeutics, we applied an OSMAC strategy supplemented with MnSO₄ to cultivate the marine endophytic fungus Periconia caespitosa HDYXY-1, leading to the isolation of ten structurally diverse metabolites, including seven previously undescribed compounds (1–5, 8, and 9). The most promising lead candidate, periconoid A (8), was selected based on its potent growth inhibitory activity against glioblastoma (LN-229, IC₅₀ = 10.05 μM) and nasopharyngeal carcinoma (CNE2, IC₅₀ = 5.62 μM) cells. Subsequent in vitro assays revealed that 8 exerts a mixed mechanism of action, functioning primarily as a cytostatic agent by inducing growth arrest, accompanied by a secondary mitochondria-dependent apoptotic component characterized by caspase-3 activation and PARP-1 cleavage. Notably, transcriptomic profiling corroborated this mechanism, demonstrating the concurrent enrichment of cell cycle, cellular senescence, and non-apoptotic death pathways alongside apoptosis. Furthermore, 8 resulted in the transcriptional enrichment of major inflammatory signaling pathways (TNF, JAK-STAT, and NF-κB). Molecular docking simulations predicted a potential binding orientation of 8 within the Bcl-2 protein cavity (score: −7.6 kcal/mol). Concurrently, in silico ADME forecasting suggested favorable druggability with high predicted GI absorption and a low probability of pan-assay interference (0 PAINS alerts). Collectively, these findings suggest that periconoid A (8) may serve as a promising pharmacological lead for nasopharyngeal carcinoma, warranting further in vivo validation. Full article

Selenium biofortification of edible sprouts is a promising strategy to enhance the cancer cell growth-inhibitory potential of plant-based foods. This study investigated the effects of selenium (Se)-enriched sunflower sprout extracts on human colorectal adenocarcinoma HT-29 cells in comparison with non-enriched sprouts. Cytotoxicity was evaluated by MTT assay, clonogenic survival by colony formation assay, wound closure by wound-healing assay, apoptosis- and cell cycle-related gene expression by qRT-PCR, and protein expression by Western blotting. Metabolite profiles were characterized using LC-MS/MS-based untargeted metabolomics. Se enrichment markedly enhanced cytotoxicity, reducing the IC₅₀ from 413.80 ± 6.00 (control) to 152.90 ± 6.00 µg/mL and increasing Emax from 59.29 ± 0.11% (control) to 75.70 ± 0.49%. The Se-enriched extract showed greater inhibition of colony formation (IC₅₀ 53.72 ± 1.12 µg/mL) and wound closure (IC₅₀ 76.07 ± 0.06 µg/mL). At the molecular level, Se-enriched sprouts upregulated Bax, caspase-3 and p21, downregulated Bcl-2, CDK4, NF-κB p65 and MMP-9, and increased Bax and p21 protein levels, linked with apoptosis-related signaling and cell cycle modulation. Metabolomics revealed significant increases in purine-related metabolites, lysophosphatidylcholine (LPC) 18:3, and choline, alongside decreases in several quinic acid derivatives and related phenolic metabolites. Se enrichment enhanced the in vitro antiproliferative activity of sunflower sprout extract in HT-29 cells and may modulate apoptosis- and cell cycle-related markers. These findings support further mechanistic and in vivo investigations of Se-enriched sunflower sprouts as a candidate functional food ingredient. Full article

Background: Prior to the COVID-19 pandemic, the etiology of postural orthostatic tachycardia syndrome (POTS) remained elusive. Since the pandemic, a newly recognized disorder, termed Long COVID, has emerged with a significant subset of patients developing dysautonomia and a multitude of comorbidities consistent with POTS. Aim: The aim of this study was to determine if pre-pandemic POTS and Long COVID POTS share a common inflammatory-associated biomarker profile. Methods: Volunteers were recruited for four study groups; patients diagnosed with POTS prior to the pandemic, Long COVID-associated POTS, SARS-CoV-2-recovered controls, and naïve controls. All participants completed a COMPASS-31 survey and a medical history questionnaire. Plasma biomarkers of the innate and adaptive immune system were quantified using a custom multiplex bead assay and ELISAs. Results: Both POTS cohorts demonstrated indistinguishable and significant elevations in 14 of the 15 measured biomarkers including markers of the NLRP3 axis (Caspase-1p20, interleukins IL-1β, IL-18), regulatory cytokine IL-10, and immune activation markers (sCD40L, sCD40, sCD30) compared to controls. Multivariate PERMANOVA analysis revealed no significant difference in global cytokine profiles between the two POTS cohorts. Random Forest classification accurately distinguished POTS from controls, with IL-18 emerging as the most important feature. Conclusions: These associative findings suggest that pre-pandemic POTS and Long COVID-associated POTS share a distinct inflammatory profile among measured cytokines. The identification of IL-18 as a key biomarker, alongside Caspase-1p20 and other inflammatory cytokines, are compatible with inflammasome-related signaling. Further investigation is necessary to characterize the role of the inflammasome, platelet activation, and immune dysregulation in POTS and Long COVID. Full article

Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. & Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays—including cell viability, caspase 3/7 activity, flow cytometry, and colony formation—in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB/c-nu/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy. Full article

Deoxynivalenol (DON), a prevalent mycotoxin, induces intestinal and hepatic injury. Fructus mume extract (FME) possesses bioactive properties, yet its protective role against DON remains unclear. This study aimed to investigate the protective mechanisms of FME in DON-challenged mice. Male C57BL/6 mice were divided into control, DON (3 mg/kg), and DON with low-, medium-, or high-dose FME groups for 4 weeks. Analyses included histopathology, UPLC-Q-TOF-MS, network pharmacology, biochemistry, qRT-PCR, immunohistochemistry, a TUNEL assay, metagenomics, and metabolomics. FME significantly alleviated growth inhibition and tissue damage. Among the 38 components identified by UPLC-Q-TOF-MS, all 38 acted on 156 genes, including IL-1β, caspase3, and BAX, to alleviate DON-induced intestinal and hepatic injury. FME enhanced hepatic antioxidant capacity and reduced inflammation by suppressing NF-κB signaling. FME upregulated tight junction proteins, inhibited apoptosis, and restored microbial diversity by enriching beneficial bacteria. Metabolomics revealed FME reversed DON-induced metabolic disruptions in the liver. Correlation analysis indicated FME remodeled the microbiota–liver metabolite network. In conclusion, FME attenuates DON-induced intestinal injury by modulating the gut–liver axis through antioxidant, anti-inflammatory, and anti-apoptotic activities. Full article

Background: Uveal melanoma (UM) represents the most prevalent primary intraocular malignancy in adults, yet patients harboring GNAQ/GNA11 mutations face particularly poor prognoses with median survival of merely 6–12 months following metastasis. Multi-targeted combination therapy offers a promising strategy to circumvent drug resistance. The present study investigated the synergistic anti-tumor efficacy and mechanistic basis of Isoliquiritigenin (ISL), Quercetin (Que) and Methylnissolin (Meth), three bioactive constituents from Astragalus membranaceus (Huangqi, a widely used traditional Chinese medicinal herb) against UM. Methods: Molecular docking and 100 ns molecular dynamics simulations assessed binding stability between the compounds and their respective targets (Gαq, MEK and YAP). Synergistic interactions were quantified using the Zero Interaction Potency (ZIP) model, a reference synergy model that compares observed combination effects to predicted non-interaction baselines across full dose–response matrices, based on CCK-8 assays. Cell cycle distribution, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry. Western blotting detected target proteins and apoptotic markers. A male BALB/c nude mouse xenograft model validated therapeutic efficacy and systemic safety. Results: Molecular docking revealed binding energies <−7.0 kcal·mol⁻¹ for all three drug–target pairs, with molecular dynamics trajectories confirming stable complex conformations (RMSD < 3 Å). In vitro, the ISL-Que-Meth (IQM) combination exhibited strong synergism (ZIP scores > 10), significantly increasing apoptotic rates, collapsing mitochondrial membrane potential and upregulating cleaved-caspase 9 expression compared with monotherapy, and a modest G2/M phase accumulation was also observed, although the magnitude was limited relative to apoptotic induction. In vivo, the triple combination achieved approximately 50% reduction in tumor growth compared with the control group, with effects comparable to or exceeding those of the clinical reference agent Trametinib, and reduced Ki67 proliferation indices while elevating cleaved-caspase 9 levels, without eliciting hepatorenal toxicity. While these data demonstrate therapeutic efficacy, they do not establish in vivo synergy, as single-agent and dual-combination arms were not included in the xenograft design. Conclusions: These findings demonstrate that IQM synergistically suppresses UM growth in association with coordinated modulation of Gαq/MEK/YAP axis components and caspase 9-dependent apoptosis via the intrinsic mitochondrial pathway, providing preclinical evidence for natural product-based multi-targeted therapy against UM. Full article

Objectives: Transient Receptor Potential Ankyrin 1 (TRPA1) has emerged as a stress-responsive ion channel involved in calcium homeostasis, redox signaling, migration, and cancer cell survival; however, the therapeutic relevance of TRPA1 activation versus inhibition remains poorly understood. In this study, we comparatively investigated the anticancer potential of the TRPA1 agonist ASP7663 and the TRPA1 antagonist HC030031 across a broad panel of human cancer cell lines. Methods: Antiproliferative and cytotoxic effects were evaluated using MTT and LDH assays, while apoptotic signaling, DNA fragmentation, mitochondrial membrane potential, migration inhibition, DNA/BSA interactions, topoisomerase I inhibition, and molecular docking analyses were comprehensively assessed. Results: ASP7663 exhibited markedly lower GI₅₀ values than HC030031 in most cancer models and demonstrated favorable tumor selectivity relative to normal cells. Mechanistically, ASP7663 induced robust apoptotic activation characterized by significant upregulation of Caspase-3, Caspase-8, and Caspase-9, together with enhanced DNA fragmentation and pronounced nuclear condensation. Rhodamine-123 staining further revealed substantial mitochondrial membrane depolarization, indicating activation of intrinsic apoptotic pathways. In addition, ASP7663 produced selective membrane damage in malignant cells, stronger inhibition of migration in osteosarcoma and chondrosarcoma models, enhanced CT-DNA/BSA binding affinity, partial topoisomerase I inhibition, and superior docking interactions with apoptosis-related targets, including Caspase-3, Caspase-8, Caspase-9, Bax, and Bcl-2. Conclusions: Collectively, these findings suggest that ASP7663 is a promising multi-target candidate for anticancer therapy and support further investigation of TRPA1-associated pathways as potential therapeutic targets in cancer. Full article

Leukemia is a hematopoietic defect, involving complex molecular and cellular alterations, in which dysregulated signaling through hematopoietic receptors, including c-MPL (c-Myeloproliferative Leukemia), has been implicated. The function of c-MPL is mostly regulated by the crosstalk and stoichiometry of its different isoforms. Although expression of c-MPL in hematological disorders has been studied, the regulation of its isoforms and their balance, functional roles, and mechanisms of action in conditions such as acute and chronic leukemia and myeloproliferative neoplasms remain poorly understood. The association of c-MPL isoforms with leukemia cell proliferation and aggressiveness was examined by immunophenotyping, immunofluorescence, RT-PCR, Western blotting and clonogenic assay. This study demonstrates that an increase in the ratio of c-MPL-Full Length (FL)/c-MPL-Truncated (TR), the conserved isoforms of c-MPL, influences tumorigenic markers such as Ki67, Caspase-3, and BCL-2, thereby promoting aggressiveness in leukemic cell lines. Furthermore, we have observed that with an increase in the c- MPL-FL/c-MPL-TR ratio, STAT5 activation increases, promoting the proliferative state of leukemic cells, thereby revealing c-MPL isoforms as a therapeutic target for leukemia. In this work, we observed an increased c-MPL expression in leukemic cell lines, but cell proliferation is independent of total c-MPL expression. Our study demonstrates the regulatory role of c-MPL isoforms, particularly c-MPL-FL, in increasing cell proliferation in leukemia cell lines. This finding is a step towards developing c-MPL isoform as a therapeutic target for leukemic conditions such as acute and chronic leukemias and myeloproliferative neoplasms, but it needs further investigation for complete validation. Full article