Anthracycline-induced cardiotoxicity (AIC) remains a dose-limiting complication of cancer treatment, often leading to irreversible heart failure, yet effective cardioprotective therapies remain limited. Graph-driven drug repurposing offers a rapid pathway to identify cardioprotective therapies, but different computational models often generate divergent candidate lists that exceed experimental validation capacity. We applied a novel "Union-then-Filter" framework to prioritize therapeutics for AIC using AI-based approaches and evaluated candidates in zebrafish models. Three state-of-the-art graph learning models (TxGNN, CompGCN, and RLR) were trained on the PrimeKG to generate an initial candidate pool. A Large Language Model (LLM) agent automated evidence synthesis across 4,286 PubMed abstracts for the top 50 drugs from each model. Candidates were stratified using dual decision criteria and filtered against existing clinical trials. The pipeline narrowed 150 initial candidates to four novel candidates: Cysteine, Dasatinib, Tranilast, and Tretinoin. Prospective in vivo validation was subsequently conducted using an adult AIC (aAIC) zebrafish model. Phenotypic screening via echocardiography revealed that Cysteine, Tranilast, and Tretinoin significantly restored ejection fraction (EF) (overall one-way ANOVA: \(\:F\left(\text{4,95}\right)=47.66,\:\:p<0.0001\); Tukey's post hoc: \(\:\:\:p<0.01\) for all three treatments vs. DOX+ control) and normalized cardiac remodeling markers in doxorubicin-treated subjects (Kruskal-Wallis: \(\:{\chi\:}^{2}\left(4\right)=17.21,\:\:p=0.0018\); Dunn's post hoc: \(\:\:\:p<0.01\) for all three comparisons vs. DOX control). This study demonstrates the translational utility of an LLM-integrated AI pipeline for drug repurposing and highlights zebrafish AIC as an efficient bridge between in silico prediction and in vivo phenotypic validation in cardio-oncology.

Our Goal is to sensitize human colorectal cancer (CRC) to the differentiation-inducing effects of retinoic acid (RA) agents by suppressing WNT signaling. Previously, we reported that the WNT and RA pathways are functionally linked, and in CRC, APC mutation generates a WNT:RA imbalance leading to incomplete differentiation and stem cell (SC) overpopulation. Hypothesis: Therapeutically inhibiting WNT signaling enhances the ability of retinoid agents to induce growth suppression and differentiation. We tested drug combinations of: (1) anti-WNT agents (Sulindac & Piroxicam) that produce anti-tumor activity in humans and animals harboring germline APC mutations, with (2) RA agents (All-trans-RA, 9-cis RA) and RA metabolism blocking agent (CYP26A1 inhibitors Liarozole and Talarozole), which inhibit proliferation and induce differentiation of CRC cell lines. Results: The combined effect of anti-WNT agents and RA drugs shows additive or synergistic responses in CRC cell lines compared to single agents. Drug combinations decrease the proportion of aldehyde dehydrogenase-positive SCs and increase neuroendocrine cell differentiation in CRC cells that show a synergistic response to treatment. NanoString profiling shows that therapeutically decreasing WNT signaling in CRC cells significantly changes the effect of RA signaling on gene expression. Treating human CRC organoid cultures and PDX mouse models with WNT:RA-based drug combinations led to greater anti-tumor activity as compared to individual agents. Conclusion: Inhibiting WNT signaling effectively sensitizes CRC cells to the anti-tumor effects of retinoids. These findings have important clinical significance for designing new drug combinations against CRC.

Chikungunya virus (CHIKV) has reemerged as a global pathogen causing serious public health threat, particularly due to the absence of specific antivirals. Retinoids, vitamin A derivatives, have demonstrated antiviral potential against different viral infections, yet their efficacy against alphaviruses has never been investigated. In this study, tretinoin (TR), or all-trans retinoic acid (ATRA), was evaluated for its anti-CHIKV activity using in vitro, in vivo, and ex vivo models. TR abrogated CHIKV infection efficiently in Vero and C2C12 cells, with a marked reduction (>90%) in viral RNA, proteins, and progeny formation. The IC50 of TR against CHIKV was estimated to be 20.05 µM and 19.71 µM in Vero and C2C12 cells, respectively. Additionally, TR showed remarkable virucidal activity and effective inhibition during entry, as well as in the early stages of post-CHIKV infection. Next, the global transcriptome profile demonstrated that the "signaling by retinoic acid" pathway was significantly enriched after CHIKV infection, and retinoic acid receptors (RARs), specifically RAR-β, are the key mediators for the anti-CHIKV effect of TR. Further, the drug alters phosphorylated mitogen-activated protein kinases (MAPKs), NF-κB, and proinflammatory cytokines during CHIKV infection in RAW 264.7 cells. Interestingly, TR protected C57BL/6 mice from CHIKV challenge by diminishing viral burden, leading to reduced clinical scores and better survival. Similar observations were also noticed in the ex vivo models of CHIKV-infected primary human skeletal muscle myoblasts (HSMMs). In conclusion, this work demonstrated the repurposing potential of TR against CHIKV infection for the first time, encouraging its clinical validation toward future therapeutics.

Graft-versus-host disease (GVHD) remains a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Donor hematopoietic progenitor cells reconstitute the recipient's immune system after transplant, and newly generated donor-derived immune cells actively participate in propagating alloimmunity. Retinoic acid (RA) has well-known effects on the differentiation and proliferation of myeloid progenitor cells. We hypothesized that RA influences the reconstitution of some donor-derived myeloid cell populations after allogeneic HSCT. In a C57BL/6 into Balb/c murine allogeneic bone marrow transplantation (BMT) model, we found that Gr1[+]CD11b[+]CD84[+]F4-80[-] myeloid-derived suppressor cells (MDSCs) accumulated in the spleen of recipient mice early after BMT. Notably, the absolute number of MDSCs was significantly reduced in RA-treated mice compared with DMSO-treated mice. Furthermore, MDSCs isolated from RA-treated recipient mice showed decreased immunosuppressive function in mixed lymphocyte reactions (MLRs). Bulk RNA-sequencing (RNA-seq) revealed that RA treatment alters transcriptional programs involving Wnt signaling and the CCL2-CCR2 axis in MDSCs. We found that adding RA to the MDSC culture promotes the differentiation of Ly6C[-]Ly6G[+] granulocytic MDSCs. Thus, enhancing RA signaling causes both quantitative and qualitative changes of MDSCs after allogeneic HSCT. Recent studies have demonstrated an important role of donor intestinal CD103[+] dendrite cells (DCs) in propagating GVHD. We found that RA-treated recipient mice had significantly increased colonic CD103[+] DCs compared with DMSO-treated mice. On the contrary, vitamin A deficiency was associated with a significant reduction in the percentage and absolute number of CD103[+] DCs. To study the effects of RA on DCs in vitro, BM cells were cultured in the presence of GM-CSF. There was a significant increase in the percentage of CD11c[+]CD103[+] mucosal DCs in cultures exposed to RA. Furthermore, RA-exposed DCs exhibited increased MHC-II expression and enhanced T-cell stimulatory capacity. In summary, our study demonstrated that RA participates in regulating donor MDSC and colonic CD103[+] DC reconstitution after allogeneic HSCT. Therapeutic modulation of RA signaling or its downstream pathways may represent a strategy to limit alloimmunity and improve transplant outcomes.

Background and Objectives: Oral alitretinoin (9-cis-retinoic acid), a dual retinoic acid receptor/retinoid X receptor agonist, is approved for severe chronic hand eczema (CHE) refractory to potent topical corticosteroids but is also prescribed off-label in routine practice. Long-term real-world data on both uses are limited. We evaluated 10-year prescribing patterns, effectiveness, tolerability, and lipid changes at one Korean academic center. Materials and Methods: Patients prescribed oral alitretinoin between January 2016 and December 2025 were identified from the hospital prescribing database; those with an evaluable course of ≥1 month formed the effective-treatment cohort and underwent chart review. Treatment success was defined as final chart-derived Investigator Global Assessment (IGA) 0/1. Success by initial dose was compared using Fisher exact test; paired lipid changes using paired t-test and Wilcoxon signed-rank test. Results: Of 161 patients, 38 (23.6%) received a single prescription; 99 formed the effective-treatment cohort (50 women, 49 men; mean age 50.7 ± 16.0 years). CHE was the leading indication (70/99, 70.7%), followed by palmoplantar pustulosis (PPP, n = 14), mycosis fungoides (MF, n = 6), parapsoriasis, porokeratosis, palmoplantar keratoderma, and Darier disease. Overall success was 66.7% (66/99) over a mean treatment duration of 12.4 months, highest in CHE (77.1%) and more variable off-label (PPP 42.9%; MF 33.3%). Initiation at 30 mg was associated with higher success than 10 mg (71.1% vs. 43.8%; p = 0.044), but this association did not persist after restriction to patients maintained on their initial dose (62.2% vs. 50.0%; p = 0.498) or after Firth penalized logistic regression adjusting for age, sex, and indication (adjusted odds ratio 1.84; 95% CI 0.56-5.90; p = 0.309). Adverse events occurred in 21 patients (21.2%), most commonly dyslipidemia (n = 12) and headache (n = 7); mean triglyceride rose 42.1 mg/dL and total cholesterol 14.0 mg/dL (both p < 0.001), and new elevation above conventional thresholds occurred in 25.8% (triglyceride) and 27.5% (total cholesterol) of patients with normal baseline values. Thirty patients (30.3%) discontinued, most often for insufficient effectiveness. Conclusions: Alitretinoin showed favorable effectiveness in CHE and variable, exploratory responses off-label. The apparent advantage of 30 mg initiation was not independent of indication and dose adjustment. Lipid elevation was common, supporting routine surveillance. Off-label findings, particularly in PPP and MF, should be interpreted cautiously given small subgroups and non-standardized retrospective assessment.

Drug resistance in acute promyelocytic leukemia (APL) remains clinically challenging despite the success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. Existing explanations, including promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) mutations and alterations in individual death pathways, do not fully account for the heterogeneity of resistant phenotypes. This review proposes regulated cell death network (RCDN) remodeling as a testable framework for APL resistance. RCDN remodeling is defined as coordinated changes in network coupling, stress routing, and cellular death thresholds. We hypothesize that resistance emerges from coordinated adaptation across redox, survival signaling, and mitochondrial gating, rather than from defects in any single pathway. This predicts coupled shifts across multiple death modules and non-additive responses to combinatorial perturbations, distinguishing network-level remodeling from pathway-specific resistance. We further define experimental criteria for distinguishing network-level remodeling from pathway-specific resistance and discuss Tanshinone IIA (Tan IIA) as a preclinical multi-node perturbation probe.

Acute promyelocytic leukemia (APL) predominantly affects younger patients with significantly prolonged survival. Therefore, controlling the incidence of secondary hematological malignancies represents a crucial therapeutic goal. Secondary, acute T-lymphoblastic leukemia (T-ALL) following APL is rare and confers a poor prognosis, with only 2 cases reported to date. Herein, we present a case of a young female with APL who attained complete remission (CR) after receiving dual induction therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), followed by standard consolidation and maintenance treatment cycles. After discontinuing chemotherapy for 26 months, the patient conceived naturally and was later diagnosed with T-ALL in the first trimester of pregnancy. She attained a second CR after receiving the VDCLP chemotherapy regimen (vincristine+daunorubicin+cyclophosphamide+L-asparaginase+prednisone). She subsequently underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) and remained in sustained CR at the 18-month follow-up time point. For patients with T-ALL secondary to APL after treatment remission, early diagnosis combined with the VDCLP regimen and allo-HSCT demonstrated certain therapeutic efficacy.

Retinoic acid, the active metabolite of vitamin A, is a pleiotropic signaling molecule that integrates developmental, homeostatic, and pathological processes across multiple organ systems. During embryogenesis, RA gradients regulate tissue patterning and lineage commitment, while in adult tissues, RA contributes to epithelial integrity, stem-cell regulation, immune homeostasis, and metabolic balance. Disruption of retinoic acid synthesis, degradation, receptor signaling, or pathway crosstalk underlies a broad spectrum of diseases, including congenital malformations, autoimmune and inflammatory conditions, neurodegenerative disorders, cardiovascular disease, pulmonary and ophthalmic pathologies, and cancer. In the tumor, RA signaling exhibits remarkable plasticity, acting as either a differentiation inducer or a stemness-maintaining factor, depending on genetic, metabolic, and microenvironmental cues. Therapeutically, retinoid-based interventions have revolutionized the treatment of acute promyelocytic leukemia. Still, their broader application has been constrained by resistance mechanisms, pharmacokinetic limitations, tissue-specific effects, and the dual nature of retinoic acid signaling across different disease states. Advances in organoid systems, single-cell and spatial transcriptomics, and multimodal epigenomics are revealing highly localized and cell-type specific retinoid responses, supporting a systems-level model of RA signaling. This framework defines "retinoid endotypes" as tissue- and stage-specific states shaped by retinoid metabolic niches, chromatin state, and microenvironmental organization, with potential to guide patient stratification and precision retinoid therapy.

During embryogenesis, morphologically diverse epithelial organs bud from different regions of the embryonic gut. The unique features of each nascent organ result from distinct cell fate specification and morphogenetic events elicited by organ-inducing cues. Retinoic acid is a powerful inducer of the pancreas, yet how it regulates pancreas specification and budding from the foregut endoderm remains poorly understood. By modeling these processes using a new human embryonic stem cell (hESC) organoid system, we demonstrate that both pancreas budding and specification are induced by RAR:RXR signaling. On the molecular level, we identify β-catenin as an important downstream target and propose that the reduction of β-catenin at the cell membrane weakens cell-cell adhesion (resulting in perturbed apical-basal cell polarity and gut epithelium multi-layering), while its nuclear depletion relieves β-catenin-mediated repression of FOXA2-dependent Pdx1 transcriptional activation. Our findings provide a new framework by which developmental cues coordinate both morphogenetic and cell specification events by targeting proteins with dual roles in cell-cell adhesion and transcription, such as β-catenin.

Intestinal dendritic cells (DCs) play a central role in maintaining gut tolerance through priming of peripheral regulatory T cells (pTreg cells). DC tolerogenicity has been linked to catabolic metabolism, but the role of AMP-activated kinase (AMPK), a key regulator of catabolic metabolism, in regulating intestinal tolerance remains unclear. We found high AMPK activation in intestinal DCs, and loss of AMPKα1 in CD11c-expressing cells (CD11c[ΔAMPKα1]) led to reduced frequencies of intestinal RALDH[+] CD103[+] cDC2s. This was associated with reduced pTreg cell induction and consequently increased type 2 immunity in models of intestinal helminth infection. Correspondingly, CD103[+] cDC2s from helminth-infected CD11c[ΔAMPKα1] mice failed to prime Treg cells ex vivo. Similarly, Treg cell induction by AMPK-deficient human retinoic acid (RA)-induced tolerogenic CD103[+] DCs was compromised. Mechanistically, AMPK underpinned RA-driven tolerogenicity by promoting RALDH activity and TGF-β secretion in a FoxO3-dependent manner, independent from metabolic reprogramming. Our findings identify AMPK as a key regulator of intestinal DC-mediated tolerance and as a therapeutic target to counter intestinal inflammatory disease.

Persistently poor glioblastoma (GBM) survival necessitates better elucidation of tumor drug responses. After observing that low curcumin and all-trans retinoic acid (ATRA) doses stimulated cell proliferation and counteracted each other's high-dose antiproliferative effects in U87 GBM cells, drug influences on cell growth, migration, and death and the antiproliferative interaction proteome were further studied. Cell proliferation and migration were assessed by xCELLigence Real-Time Cell Analysis (RTCA). Cell death was defined using flow cytometry. Drug interactions were determined with CompuSyn software (version 1.0). Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), High-Performance Liquid Chromatography (HPLC), and SequestHT software (version 1.4) were utilized for peptide generation and identification. ATRA at high doses inhibited cell growth and migration more efficiently. Curcumin was more proliferative and antagonistic against anti-growth effects at low doses. Migration inhibition and apoptosis occurred synergistically at the highest drug doses. ATRA influenced the proteome more remarkably, reducing Transforming Growth Factor Beta Induced (TGFBI), Phosphoglycerate Dehydrogenase (PHGDH), tenascin, and Sequestosome 1 (SQSTM1). These effects were alleviated by curcumin, except for SQSTM1. Uveal Autoantigen With Coiled-Coil Domains And Ankyrin Repeats (UACA) and Sad1 And UNC84 Domain Containing 2 (SUN2) were increased by ATRA and curcumin, and to a lesser extent by the combination. Hexokinase 2 (HXK2) was increased by curcumin and the combination. Heme Oxygenase 1 (HMOX1) was depleted by the combination, but not by the single agents. SQSTM1 and HMOX1 reductions may mediate anticancer synergism, while the remaining changes may indicate ongoing hormetic pathways not reflected in cell counts.