Ovarian cancer is one of the most lethal gynecological diseases owing to its poor prognosis and lack of clear symptoms. Cisplatin is commonly used as the primary chemotherapeutic drug for ovarian cancer. However, chemoresistance to cisplatin in advanced ovarian cancer is a major factor contributing to chemotherapy failure. Pyruvate kinase M2 (PKM2) is significantly upregulated in ovarian cancer tissues, thereby contributing to cisplatin resistance. Despite this, its therapeutic role remains unclear. This study aimed to evaluate whether shikonin and compound 3K, PKM2 inhibitor, could enhance anticancer effects in cisplatin-resistant ovarian cancer SKOV-3 cells by regulating autophagic pathways. Cytotoxicity assays using MTT and colony formation assays demonstrated that shikonin or compound 3K treatment significantly reduced PKM2 expression in SKOV-3 cells. Shikonin and compound 3K inhibited PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, resulting in significant suppression of cell proliferation and survival. Additionally, Shikonin and compound 3K treatment suppressed PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, as evidenced by increased LC3-II expression, autophagosome formation, and reduced cell viability. These findings strongly suggest that PKM2 overexpression plays a key role in cisplatin resistance in ovarian cancer. Thus, PKM2 inhibitors use may be a highly effective strategy for overcoming chemoresistance and improving outcomes in patients with advanced ovarian cancer.

A mixture of 5-chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) is frequently utilized as a biocide in various personal care products (PCP). However, toxicity attributed to this mixture remains poorly understood. Therefore, this study aimed to investigate effects of CMIT/MIT on the respiratory system using human bronchial epithelial BEAS-2B cells as a model. In this study, the mechanisms underlying CMIT/MIT-induced toxicity were examined with particular focus on mitochondria-mediated apoptotic and autophagy cell death using BEAS-2B cells. Notably, CMIT-MIT initiated cytotoxic effects on BEAS-2B cell viability at concentrations of 10 μg/mL following 1 h treatment. In addition, CMIT-MIT treatment inhibited complex II in a concentration-dependent manner, diminished mitochondrial membrane potential and altered dynamic balance between mitochondrial fission and fusion indicative of mitochondrial damage. Further, exposure to 10 μg/mL CMIT-MIT for 1 h induced cellular damage, elevated mitochondrial reactive oxygen species (ROS) levels and concomitantly increased levels of apoptosis and autophagy. Taken together our findings indicate the potential of CMIT/MIT exposure to disrupt mitochondrial functions, thereby initiating apoptotic and autophagic processes in human bronchial epithelial BEAS-2B cells.

Human alveoli constitute most of the lung parenchyma and play a pivotal role in respiratory diseases. Traditional alveolar type 2 epithelial cells, such as A549 and H441, have been widely used to study pulmonary toxicity mechanisms. However, these cells have inherent limitations, including insufficient barrier function, lack of functional surfactant protein expression, and failure to recapitulate the physiological features of human alveolar epithelial cells. Here, we established differentiated AEC2s (diff-AEC2s) from human embryonic stem cells and validated their stage-specific differentiation. We confirmed key AEC2-like features in vitro, including lamellar body-like organelles, higher TEER values, and increased AEC2 marker expression relative to A549 and H-6053 cells under ALI culture. The diff-AEC2s were treated with bleomycin to evaluate their potential for modeling disease-related epithelial injury. Transcriptomic analysis with benchmark dose showed epithelial stress related to DNA damage and cell cycle arrest quantitatively. Bleomycin also induced the dose-dependent alterations of alveolar epithelial and damage-related markers, including LGALS3, KRT8, CTGF, and senescent phenotypes. This study presents a human stem cell-derived alveolar epithelial platform to quantify early epithelial stress and injury-associated responses in vitro.

Ovarian cancer is among the most lethal gynecological malignancies due to its poor prognosis and lack of early symptoms. Cisplatin remains the primary chemotherapeutic agent; however, resistance to cisplatin in advanced ovarian cancer is a major cause of treatment failure. Pyruvate kinase M2 (PKM2) is markedly upregulated in ovarian cancer tissues and contributes to cisplatin resistance, though its therapeutic relevance has not been fully defined. This study investigated whether shikonin and compound 3K, both PKM2 inhibitors, could enhance anticancer effects in cisplatin-resistant SKOV-3 cells by modulating autophagic pathways. Cytotoxicity assays revealed that treatment with shikonin or compound 3K significantly reduced PKM2 expression. Combination therapy with high-dose PKM2 inhibitors and cisplatin increased apoptosis compared to controls, although the modest induction suggests apoptosis is only partially responsible for the observed effects. Additionally, Shikonin and compound 3K treatment suppressed PKM2-mediated glycolysis and induced autophagic cell death in cisplatin-resistant ovarian cancer cells, as evidenced by increased LC3-II expression, autophagosome formation, and reduced cell viability. These findings indicate that PKM2 overexpression plays a central role in cisplatin resistance in ovarian cancer. Targeting PKM2 with inhibitors such as shikonin or compound 3K may represent a promising strategy to overcome chemoresistance and improve therapeutic outcomes in patients with advanced ovarian cancer. These findings strongly suggest that PKM2 overexpression plays a key role in cisplatin resistance in ovarian cancer. Thus, PKM2 inhibitors use may be a highly effective strategy for overcoming chemoresistance and improving outcomes in patients with advanced ovarian cancer.

Liver fibrosis remains an unmet medical need with limited therapeutic options and high translational failure. Conventional two-dimensional stellate cell cultures and cytokine-induced organoids poorly recapitulate in vivo pathology. Here, we establish a physiologically relevant liver fibrosis model by generating organoids directly from carbon tetrachloride (CCl₄)-injured fibrotic mouse liver tissue. These disease-derived organoids preserved key pathological hallmarks, including extracellular matrix remodeling and metabolic dysfunction, showing strong transcriptomic resemblance to fibrotic liver tissue. Using a two-tier screening pipeline, candidate natural products were first evaluated in hepatic stellate cells (in vitro) and subsequently validated in organoids (ex vivo) and murine fibrosis models (in vivo). Sargassum japonica (S. japonica) consistently demonstrated anti-fibrotic efficacy across all models, suppressing collagen deposition and α-SMA expression while restoring hepatic metabolic metabolism. RNA-sequencing revealed concordant downregulation of fibrosis-associated pathways and reactivation of detoxification and lipid metabolism genes, indicating dual mechanisms of action: inhibition of fibrogenesis and promotion of metabolic recovery. These findings highlight S. japonica as a promising anti-fibrotic candidate, and fibrotic liver-derived organoids as a predictive platform for drug discovery and validation. This integrated pipeline provides a translational bridge between in vitro assays and in vivo disease models, accelerating the identification of novel therapeutics for chronic liver disease.

Abstract Background: Histone lysine demethylase 4B (KDM4B), a key histone lysine demethylase, is aberrantly overexpressed in breast cancer and functions as an essential epigenetic co-activator of ERα signaling. Although its oncogenic role in breast tumorigenesis has been established, the functional distinctions and underlying molecular mechanisms of KDM4B in tamoxifen-sensitive versus tamoxifen-resistant states remain poorly defined. Elucidating KDM4B’s contribution to the evolution of endocrine resistance will be critical for identifying novel therapeutic targets and advancing precision strategies to overcome resistance to endocrine therapy. Methods: KDM4B expression across human cancers and normal tissues was evaluated using TCGA and GTEx datasets. To investigate its functional role, we compared the effects of KDM4B modulation in ERα-positive MCF-7 cells and their tamoxifen-resistant derivative, MCF-7 TamR. KDM4B was suppressed either by siRNA-mediated knockdown or by pharmacological inhibition using the selective KDM4B inhibitor B3. Cell proliferation was measured through MTT and colony formation assays. Protein expression levels of ERα, Bcl-2, H3K9me3, Cyclin D1, c-Myc, and related signaling molecules were examined via Western blotting. Cell-cycle progression and apoptosis were analyzed using flow cytometry. Metabolic reprogramming was evaluated using the Seahorse glycolytic stress test. Results: TCGA and GTEx analyses revealed that KDM4B is significantly overexpressed in breast cancer compared with normal breast tissue. Consistently, KDM4B levels were markedly elevated in tamoxifen-resistant MCF-7 (TamR) cells relative to parental MCF-7 cells. Suppression of KDM4B through siRNA-mediated knockdown or pharmacological inhibition substantially reduced the proliferative capacity and colony-forming ability of both MCF-7 and TamR cells. KDM4B depletion restored H3K9me3 enrichment, decreased ERα expression, and induced G1/S cell-cycle arrest. In addition, metabolic profiling demonstrated that KDM4B inhibition attenuated glycolytic activity, indicating a role in metabolic reprogramming. Conclusion: KDM4B serves as a critical epigenetic regulator in both tamoxifen-sensitive and tamoxifen-resistant ERα-positive breast cancer. Inhibition of KDM4B restores repressive histone marks, suppresses ERα-dependent transcription, and attenuates cellular proliferation and metabolic activity. The heightened dependence of tamoxifen-resistant cells on KDM4B further underscores its potential as a promising therapeutic target for overcoming endocrine therapy resistance. Citation Format: Tian Zheng, Ju Ri Kim, Hyun Ji Noh, Hyung Sik Kim. Epigenetic regulation of histone lysine demethylase 4B on cancer therapy in tamoxifen-sensitive and -resistant breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1938.

OBJECTIVE:Low-dose ionizing radiation (LDIR, ≤100 mGy) is a public health concern due to its extensive use in diagnostic and therapeutic imaging. This study examined somatic variants (SV) among Korean industrial radiographers exposed to LDIR using whole-genome sequencing (WGS). METHODS:WGS data from 65 workers (mean age 36.7 years) collected between 2016 and 2023 were analyzed. Participants had a mean employment duration of 12.7 years and an average cumulative radiation dose of 33.9 mSv from National Dose Registry records. SV were identified via the GATK Mutect2 single-sample workflow applied to peripheral blood-derived DNA and sequentially filtered using standard pipelines, including FilterMutectCalls, population frequency, recurrent artifacts, Funcotator annotation, and manual Integrative Genomics Viewer review. RESULTS:A total of 105 170 somatic variants were identified, with a median of 1744 variants per individual, approximately 98% of which were single nucleotide variants. Cumulative radiation dose showed a significant positive correlation with total SV burden (R=0.32, P=0.013), including both coding (R=0.34, P=0.008) and non-coding regions (R=0.31, P=0.015). Age, smoking, alcohol consumption, hypertension, and hyperlipidemia were not significantly associated with variant burden. CONCLUSIONS:These WGS-based findings provide preliminary insight into blood-derived SV patterns among occupationally exposed radiation workers. Given the small sample size, blood-only design, and absence of matched unexposed controls, the findings should be interpreted as hypothesis-generating and require validation in larger longitudinal studies with comprehensive exposure assessment.

Histone deacetylase 6 (HDAC6), a key regulator of non-histone protein acetylation and inflammatory signaling, has emerged as a potential therapeutic target in renal diseases. This study investigated the renoprotective effects of selective HDAC6 inhibition in streptozotocin (STZ)-induced diabetic nephropathy (DN) in rats. Male Sprague-Dawley rats injected STZ (60 mg/kg, i.p.) to induce diabetes, followed by treatment with the selective HDAC6 inhibitors tubastatin A (TubA, 30 mg/kg/day, i.p.) or ACY-1215 (30 mg/kg/day, i.p.) for 3 weeks after confirmation of hyperglycemia. Diabetic rats exhibited significant increases in blood glucose, blood urea nitrogen (BUN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, and triglycerides, along with severe renal histopathological alterations. Urinary biomarkers of kidney injury, including kidney injury molecule-1 (KIM-1), selenium-binding protein 1 (SBP1), and neutrophil gelatinase-associated lipocalin (NGAL), were significantly elevated in diabetic rats and were significantly reduced following treatment with HDAC6 inhibitors. Proteomic profiling identified 159 and 167 differentially expressed proteins in the TubA/STZ and ACY-1215/STZ groups, respectively, indicating partial restoration of diabetes-associated molecular dysregulation. Mechanistically, HDAC6 inhibition restored antioxidant defenses, as evidenced by increased expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), Heme oxygenase 1 (HO-1), sirtuin-3 (SIRT3), and MnSOD, reduced oxidative stress markers including advanced glycation end-products (AGEs), malondialdehyde (MDA), and 8-Hydroxy-2-deoxyguanosine (8-OHdG), suppressed Interleukin-1 beta (IL-1β) and Interleukin 6 (IL-6), attenuated apoptosis, and inhibited fibrosis and epithelial-mesenchymal transition by modulating the expression of transforming growth factor β1 (TGF-β1), vimentin, α-smooth muscle actin (α-SMA), and E-cadherin. Collectively, these findings demonstrate that HDAC6 inhibition exerts potent renoprotective effects and represents a promising therapeutic strategy for diabetic nephropathy.

Human telomerase reverse transcriptase (hTERT) is overexpressed in most human cancers and is an important target for cancer therapy. In this study, HS1002 was synthesized based on the amino acid sequences of gonadotropin-releasing hormone (GnRH) and hTERT. This study aimed to evaluate HS1002's anticancer activity and its effects on the gonadotropin-releasing hormone receptor (GnRHR) and hTERT in prostate cancer cells. HS1002 increased cytosolic calcium influx in GnRHR-overexpressing HEK293 cells and showed specific molecular docking interactions with GnRHR. Compared with prostate cancer cell lines, HS1002 exhibited the highest cytotoxicity against LNCaP cells. The hTERT expression correlated with telomerase activity was suppressed by HS1002, resulting in reduced metastasis and increased apoptosis and autophagy. Additionally, HS1002 suppressed c-Myc and ERK protein expressions in LNCaP cells. Furthermore, HS1002 inhibited tumor growth and downregulated hTERT expression in the xenograft model tumor tissues. HS1002/IL-2-pretreated PBMCs also exhibited potent cytotoxicity toward LNCaP cells. In addition, HS1002 increased the production of granzyme B and IFN-γ in CD8+ T cells in MC38 syngeneic mice. These findings demonstrate that HS1002 suppresses prostate cancer cell growth and induces anticancer immunity, suggesting its potential as a novel therapeutic agent against prostate cancer.

Deep eutectic solvents (DESs), regarded as green alternatives to volatile organic solvents, are commonly prepared by heating; however, despite the possible formation of byproducts during heating, the toxicological relevance of their preparation conditions remains unresolved. The aim of this study was to disentangle preparation-dependent in vivo toxicity from the intrinsic effects of DESs through mechanistic insights using reline-a widely used DES comprising choline chloride and urea (1:2)-as a model solvent. Two forms of reline, prepared by either heating (reline_H) or freeze-drying (reline_FD), were identical in composition and eutectic structure, except for thermally generated byproducts such as ammonia. At 1.8 g/kg (p.o.), reline_H induced corrosive symptoms and gastric injury to ICR mice, irrespective of sex, whereas reline_FD was well-tolerated. Mechanistic investigations suggested that reline_FD induces a metabolic burden inherent to the reline components. Contrastingly, reline_H caused additional perturbations, including a pronounced redox imbalance, accelerated uptake of reline, and delayed ammonia clearance, consistent with alkaline injury; moreover, it caused mitochondrial destabilization as a downstream consequence of alkaline injury. Collectively, our findings suggest that reline toxicity arises from alkaline stress caused by thermally generated byproducts, whereas freeze-drying mitigates such liabilities. With the increasing adoption of DESs in bio-relevant settings, these findings indicate that the safety of a DES not only depend on its composition, but possibly also on its preparation history. This study highlights that the preparation method of a DES as a critical yet often-overlooked determinant of DES safety, which is especially relevant when evaluating DESs for future applications.

Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants bioaccumulating in human tissues and are associated with renal dysfunction. However, the molecular mechanisms underlying PFAS-induced nephrotoxicity remain unclear. We aimed to investigate the nephrotoxic effects of representative PFAS, including perfluorooctanoic acid (PFOA), perfluorohexanoic acid (PFHxA), and perfluorohexane sulfonic acid (PFHxS), focusing on mitochondrial homeostasis in renal tubular epithelial cells and rat kidney tissues. In NRK-52E cells, PFOA and PFHxS induced dose- and time-dependent cytotoxicity accompanied by G0/G1 cell cycle arrest and intrinsic apoptosis. PFAS exposure markedly increased intracellular and mitochondrial reactive oxygen species levels, calcium levels, membrane depolarization, and apoptotic signaling. Moreover, PFAS impaired mitochondrial respiration and promoted a metabolic shift toward glycolysis. Mitochondrial dysfunction presented as reduced mitochondrial mass, disrupted mitochondrial dynamics, and decreased mitochondrial DNA copy number and common deletions. PFAS-induced mitochondrial dysfunction was accompanied by suppression of the AKT–GSK3β–CREB signaling pathway and decreased expression of mitochondrial biogenesis regulators. Quantitative proteomic analysis revealed dysregulated mitochondrial and oxidative stress-associated proteins following PFAS exposure. In vivo, oral PFAS administration induced renal injury characterized by histopathological damage, apoptotic activation, and increased levels of renal injury biomarkers. Among the tested compounds, PFOA and PFHxS exhibited the strongest nephrotoxic effects in vitro, whereas PFOA and PFHxA produced more pronounced renal injury in vivo. In conclusion, PFAS induce nephrotoxicity by disrupting mitochondrial homeostasis, oxidative stress, and suppressing the AKT–GSK3β–CREB pathway. Thus, mitochondria are central to PFAS-associated renal toxicity and may serve as potential targets for environmental risk assessment and therapeutic intervention.

Following injury, prostaglandin E2 (PGE2) drives intestinal epithelial repair by inducing revival stem cells (RSCs), which compensate for the loss of homeostatic Lgr5+ stem cells. Using intestinal organoid models, we demonstrate that melatonin potentiates the PGE2- or damage-induced RSC emergence by rewiring cellular plasticity toward a fetal-like state and sustaining pro-regenerative YAP activity, thereby enhancing overall repair capacity. To translate this finding into a therapeutic application, we developed a biohybrid heterospheroid (Mel-HS) by combining melatonin-loaded poly(lactic-co-glycolic acid) microspheres with 3D-cultured mesenchymal stem cells (MSCs), which serve as a PGE2 source. We confirmed that this biohybrid construct preserves the paracrine capacity of MSCs to secrete PGE2. Notably, Mel-HS demonstrates superior in vivo retention compared with naive 3D-MSCs, underscoring the cytoprotective effect of encapsulated melatonin in enhancing MSC viability. Furthermore, Mel-HS promoted robust RSC induction while simultaneously providing protection against inflammatory- and oxidative insults in vitro. In a colitis model, Mel-HS accelerated mucosal healing through the dual mechanisms-immunomodulation and enhanced RSC-driven repair-resulting in marked clinical improvement. Collectively, our findings highlight the therapeutic potential of enhancing endogenous regeneration with melatonin and MSCs, establishing a promising framework for next-generation biohybrid cell therapeutics in inflammatory bowel disease management.

Laser-induced plasma technology provides a novel method for generating tactile sensations without physical contact, offering precise and controlled stimulation. However, the impact of varying energy levels on human cognitive and perceptual responses is not yet fully understood. This study aimed to present tactile sensations using laser-induced plasma in a non-contact manner and investigate the cognitive characteristics linked to changes in the plasma's energy parameters, specifically Pulse Width (PW) and Set Current (SC). The experiment was conducted with 35 right-handed male and female adults in their 20 s. Tactile stimuli were presented under two conditions: Condition 1 fixed SC and varied PW, while Condition 2 fixed PW and varied SC, with each condition adjusted to produce three energy levels. Subjective evaluations included assessments of tactile intensity and vocabulary using a 5-point scale. Sixteen terms related to tactile sensations were evaluated. A two-way repeated measures analysis of variance was used to compare scores across both factors (Condition and Energy). The results showed that as the energy level increased, the perceived intensity also rose. In the vocabulary evaluation, sensations such as "Tapping" and "Rapping" were predominant, with higher scores at increased energy levels. No significant differences were observed between the two conditions for either tactile intensity or vocabulary evaluations. In conclusion, varying the energy magnitude of laser-induced plasma can produce tactile sensations of different intensities, and the parameters used in this study successfully evoked specific sensations like slow vibration.

We identified drugs or mechanisms targeting ABCB1 (or P-glycoprotein; P-gp)-overexpressing drug-resistant cancer populations, given that these cells play a key role in tumor recurrence. Specifically, we searched for Akt inhibitors that could increase cytotoxicity in P-gp-overexpressing drug-resistant cancer cells. We performed cytotoxicity assays using five cell lines: 1. MCF-7/ADR, 2. KBV20C cancer cells (P-gp overexpression, vincristine [VIC] resistance, and GSK690693-resistance), 3. MCF-7, 4. normal HaCaT cells (non-P-gp-overexpressing, VIC-sensitive, and GSK690693-sensitive), and 5. MDA-MB-231 cancer cells (non-P-gp overexpression, relatively VIC-resistance, and GSK690693-sensitive). Herein, we found that low-dose perifosine markedly and selectively sensitizes both MCF-7/ADR and KBV20C drug-resistant cancer cells exhibiting P-gp overexpression. Compared with other Akt inhibitors (AZD5363, BKM120, and GSK690693), low-dose perifosine specifically sensitized P-gp-overexpressing resistant MCF-7/ADR cancer cells. Conversely, Akt inhibitors (other than perifosine) could enhance sensitization effects in drugsensitive MCF-7 and HaCaT cells. Considering that perifosine has both an alkyl-phospholipid structure and is an allosteric inhibitor for membrane-localizing Akt-targeting, we examined structurally and functionally similar Akt inhibitors (miltefosine and MK-2206). However, we found that these inhibitors were non-specific, suggesting that the specificity of perifosine in P-gp-overexpressing resistant cancer cells is unrelated to phospholipid localizing membranes or allosteric inhibition. Furthermore, we examined the molecular mechanism of low-dose perifosine in drug-resistant MCF-7/ADR cancer cells. MCF-7/ADR cells exhibited increased apoptosis via G2 arrest and autophagy induction. However, no increase in P-gp-inhibitory activity was observed in drug-resistant MCF-7/ADR cancer cells. Single low-dose perifosine treatment exerted a sensitization effect similar to co-treatment with VIC in P-gp-overexpressing drug-resistant MCF-7/ADR cancer cells, suggesting that single treatment with low-dose perifosine is a more powerful tool against P-gp-overexpressing drug-resistant cancer cells. These findings could contribute to its clinical use as a first-line treatment, explicitly targeting P-gp-overexpressing resistant cancer populations in heterogeneous tumor populations. Therefore, perifosine may be valuable in delaying or reducing cancer recurrence by targeting P-gp-overexpressing drug-resistant cancer cells.

Dear Editor, Crypt base columnar cells(CBCs)are essential for the homeostatic renewal of the gut lining,yet they are susceptible to cytotoxic damage.1 In the absence of CBCs,alternative cell populations drive regeneration through fetal-like reprogramming and adaptive differentiation.In particular,a rare,slow-cycling cell lineage,referred to as revival stem cell(RSC),is activated by prostaglandin E2(PGE2)secreted from the stromal niche,which subsequently stimulates the YAP pathway to facilitate the regeneration.2,3 Given the critical role of RSCs in intestinal recovery,regulating cellular plasticity to drive endogenous RSCs could serve as a powerful strategy for regenerative medicine.

Triple-negative breast cancer (TNBC) remains a leading cause of cancer-related mortality in women, characterized by its aggressive nature and limited therapeutic options. TNBC is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, which excludes patients from targeted endocrine and HER2-directed therapies, contributing to poor prognosis. This study investigates BKS-112, a potent histone deacetylase 6 (HDAC6) inhibitor, for its anticancer activity against TNBC using MDA-MB-231 cells. We assessed HDAC protein expression and their prognostic implications, alongside in vitro experiments analyzing cell viability, apoptosis, autophagy, and colony formation. BKS-112 exhibited dose- and time-dependent reductions in cell viability, significant morphological alterations, and decreased colony formation. The compound increased the acetylation of histones H3, H4, and α-tubulin while downregulating HDAC6 expression and activity. Additionally, BKS-112 reduced cell migration, demonstrating anti-metastatic potential. It induced G1 phase cell cycle arrest and modulated key regulators, including cyclins and cyclin-dependent kinases (CDKs). Apoptosis was promoted through mitochondrial pathways, evidenced by changes in Bcl-2, Bax, and caspase activation. BKS-112 also elevated reactive oxygen species (ROS) levels, affecting apoptosis-related PI3K/AKT signaling. Autophagy was triggered by upregulating LC3 and Atg-7 expression. Collectively, these findings suggest that BKS-112 exerts robust anticancer effects by inducing cell cycle arrest, apoptosis, and autophagy, highlighting its therapeutic promise for TNBC treatment.

Liver toxicity poses a critical challenge in drug development due to the liver's pivotal role in drug metabolism and detoxification. Accurately predicting liver toxicity is crucial but is hindered by scattered information sources, a lack of curation standards, and the heterogeneity of data perspectives. To address these challenges, we developed the HepatoToxicity Portal (HTP), which integrates an expert-curated knowledgebase (HTP-KB) and a state-of-the-art machine learning model for toxicity prediction (HTP-Pred). The HTP-KB consolidates hepatotoxicity data from nine major databases, carefully reviewed by hepatotoxicity experts and categorized into three levels: in vitro, in vivo, and clinical, using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The knowledgebase includes information on 8,306 chemicals. This curated dataset was used to build a hepatotoxicity prediction module by fine-tuning a GNN-based foundation model, which was pre-trained with approximately 10 million chemicals in the PubChem database. Our model demonstrated excellent performance, achieving an area under the ROC curve (AUROC) of 0.761, surpassing existing methods for hepatotoxicity prediction. The HTP is publicly accessible at https://kobic.re.kr/htp/ , offering both curated data and prediction services through an intuitive interface, thus effectively supporting drug development efforts. Scientific contributions HTP-KB consolidates comprehensive curated information on liver toxicity gathered from nine sources. HTP-Pred utilizes advanced deep learning techniques, significantly enhancing predictive accuracy. Together, these tools provide valuable resources for researchers and practitioners in drug development, accessible through a user-friendly interface.

Rationale: Hair loss affects millions globally, with limited effective treatments available and significant psychological impacts. Mesenchymal stem cells (MSCs) and MSC-derived exosomes hold therapeutic potential by modulating cellular communication, reducing inflammation, and supporting hair follicular regeneration. Rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor, enhances MSC therapeutic potential by promoting the release of growth factors and signaling molecules. Thus, this study explores the benefit of priming effect of rapamycin on enhancing the function of MSC-derived exosomes to promote hair regrowth in a depilation-induced murine model. Methods: MSCs were primed with rapamycin, and exosomes were extracted from the MSC-conditioned media using ultrafiltration and poly (ethylene glycol) (PEG) precipitation. Dermal fibroblasts were treated with several doses of exosomes to evaluate the in vitro effect of rapamycin-primed MSC-derived exosomes (REXO). The depilated mice were administered exosomes via intradermal route and the hair regrowth was monitored for 15 days, followed by gene expression analysis and histological examination. Results: Dermal fibroblasts treated with REXO showed a higher proliferation rate and an increase in genes related to Wnt/β-catenin signaling, autophagy, and growth factors compared to non-primed MSC-derived exosomes (CEXO). In vivo REXO therapy via intradermal injection to the depilated areas in mice enhanced hair follicle development, hair density, and hair activation markers compared with the control and naive exosome treatments. Conclusion: REXO therapy effectively enhances hair regrowth thus this approach could offer a clinically effective therapy for hair loss treatment.

Despite global efforts to reduce plastic consumption, its usage continues to rise, leading to increased environmental contamination and heightened concerns regarding the potential health impacts of nanoplastics. Owing to their prolonged residence time in the intestine, nanoplastics contribute to prolonged exposure and absorption by intestinal epithelial cells. In this study, we examined the effects of polystyrene micro- and nanoplastics of varying sizes (20 nm-1000 nm) on colorectal cancer cells (HCT116) through a series of in vitro experiments, including cell viability assays, morphological assessments, and transcriptomic profiling. Notably, long-term exposure of HCT116 cells to small-sized (20 nm) nanoplastics at a low-dose, one that does not cause acute toxicity, led to significant morphological changes and gene expression alterations. These modifications included the upregulation of markers associated with migration, cancer stem cell (CSC) properties, and epithelial-mesenchymal transition (EMT). The enhanced expression of migration markers correlated with increased cell motility. Consistent with these in vitro findings, zebrafish models demonstrated accelerated metastasis of colorectal cancer cells following nanoplastic exposure. Collectively, these results suggest that nanoplastics may contribute to colorectal cancer progression, providing new insights into the molecular mechanisms underlying this process.