Cancer therapy-related cardiomyopathy (CTR-cardiomyopathy) is the leading noncancer late effect contributing to morbidity and mortality among adult survivors of childhood cancer. Anthracycline chemotherapy and thoracic radiotherapy are the primary treatment-related risk factors. However, substantial variability among similarly treated individuals highlights the role of germline genetic susceptibility. This review summarizes pharmacogenomic evidence for CTR-cardiomyopathy and the integration of genetic and clinical risk factors for individualized risk prediction. We searched PubMed through July 2026 for studies examining the molecular underpinnings and risk prediction in these survivors. Candidate gene studies identified associations across pathways involved in drug transport (ABCC1, ABCC2, SLC28A3), metabolism (CBR3), oxidative stress (SOD2, CYBA, NCF4), DNA damage response (RARG, XRCC5, MGMT), and inflammation (P2RX7). Genome-wide studies have identified additional loci, including HAS3, ancestry-specific signals (PHTF1/MAGI3, AGBL1), and a doxorubicin-specific locus (KCNK17). Despite progress, barriers to clinical implementation remain, including heterogeneous phenotype definitions, limited replication, especially in non-European populations, and lack of prospectively validated risk models. Integration of multi-omics approaches may improve detection of subclinical cardiac injury. Ultimately, combining polygenic and other omic risk scores with clinical factors and validating these models prospectively across diverse populations will be essential for advancing precision survivorship care.

Berberine, an alkaloid with broad bioactive properties, exerts its pleiotropic effects by modulating SIRT3, a mitochondrial NAD[+]-dependent deacetylase. This review examines the dual role of SIRT3 as a target of berberine in the management of various disorders while also addressing its associated toxicological profiles. The antihyperglycemic effects of berberine are mediated through SIRT3 inhibition, which promotes hyperacetylation of complex I subunits, degradation of MPC1, an increased AMP/ATP ratio, AMPK activation, and suppression of PEPCK1, collectively resulting in the inhibition of gluconeogenesis. In contrast, the hypolipidemic, cardioprotective, and hepatoprotective effects of berberine are associated with SIRT3 activation, which facilitating adipose tissue remodeling, enhancing β-oxidation in NAFLD, promoting lipophagy in diabetic cardiomyopathy, and mitigates doxorubicin-induced cardiotoxicity. Furthermore, berberine exhibits antitumor duality, exerting contrasting effects in colorectal cancer and hepatoma models, and demonstrates versatile mitochondrial metabolic reprogramming in polycystic ovarian syndrome. Notably, ocular toxicity associated with berberine has been linked to SIRT3 inhibition in photoreceptors cells. Overall, the therapeutic versatility of berberine is fundamentally associated with its context-dependent modulation of SIRT3, positioning it as a promising mitochondrial epigenetics modulator for conditions such as metabolic syndrome, NAFLD, and DCM. However, its therapeutic application must be carefully balanced against organ-specific toxicity risks.

How Doxorubicin (Dox) mediated damage to stem cells or cardiomyocytes contributes to cardiotoxicity and cardiac regeneration is unclear. Using a human iPSC-based model together with corresponding iPSC-derived cardiomyocytes (iCMs) revealed that iPSCs are much more sensitive against single short pulse-treatments with Dox than iCMs. Major mitochondrial impairments such as increased mitochondrial fragmentation, loss of mitochondrial membrane potential, reduced ATP levels, and altered mitochondrial DNA (mtDNA) organization, yet neither increased ROS formation, nuclear DNA damage response, nor apoptosis were detected in Dox-treated iPSCs. Whole genome transcriptome profiling revealed major differences in the transcriptional response to Dox including downregulation of genes regulating cellular homeostasis and energy metabolism. Dox exposure at the iPSC stage, termed priming here, shifts the global transcriptional landscape of iCMs towards reduced cardiac muscle regeneration, energy metabolism, muscle contraction, and increased fibrosis. Functionally, priming caused iCMs to 'memorize' this early Dox treatment resulting in reduced ATP levels, altered mtDNA organization, and in impaired contractility and oscillating Ca[2+] handling. We propose that Dox-induced mitochondrial dysfunction and transcriptional priming in stem cells alters durably cardiac and bioenergetic properties of its progeny which may impair the regenerative capacity after differentiation. This may be of particular relevance for children and teenagers undergoing chemotherapy.

Transarterial chemoembolization (TACE) necessitates the use of embolic agents with intrinsic radiopacity and controlled biodegradability to enhance therapeutic precision. In addressing the limitations inherent in current drug-eluting microspheres (DEMs), this study introduces the development of inherently radiopaque and biodegradable (DOX+Lipiodol) @PLGA @CaCO3 @Alg core-shell microspheres. These microspheres were synthesized using rotating membrane emulsification and surface-induced ion crosslinking, with calcium carbonate serving multiple roles: a solid surfactant for Pickering stabilization, an acid-neutralizing agent, and an alginate shell inducer. The microspheres successfully encapsulated iodine loads, demonstrated by CT values reaching up to 8,000 HU, and contained doxorubicin at 1.53 ± 0.12 wt.%. They exhibited prolonged radiopacity for over 14 days in vivo and showed a pH-responsive drug release pattern, releasing 90% of their payload at pH 5.2 compared to 30% at pH 7.2 over 120 h. The sequential degradation process (alginate → CaCO3 → PLGA) resulted in greater than 60% mass loss within four months, correlating with a reduction in CT attenuation. In rabbit embolization models, the microspheres achieved effective vascular occlusion and induced ischemic necrosis in ears and kidneys. CT tracking was possible without additional contrast agents, and systemic biosafety was confirmed with cell viability exceeding 90%, hemolysis below 1%, and normal hematological and histological profiles. These findings suggest that the microspheres could serve as a clinically translatable platform for image-guided TACE, integrating occlusion, therapy, and monitoring into a cohesive treatment strategy.

Exercise's effect on Dox-induced cardiac senescence in the heart was investigated using p16-3MR transgenic mice. Mice treated with doxorubicin (Dox) had decreased cardiac function, increased p16INK4a + and b-Galactosidase+ senescent cells in the heart, decreased HMGB1 and calreticulin expression, endothelial cell senescence, and decreased TUJ1 expression (indicating reduced axonal density), increased expression of Semaphorin3A and p-cofilin with impaired F-actin depolarization and cytoskeleton disorganization. None of these changes were seen in mice treated with Dox + Exercise. Exercise sustained the levels of FNDC5 in the heart compared with the Dox-treated hearts suggesting a link between exercise, decreased senescence, and the FNDC5/ irisin pathway. In vitro studies using human cardiomyocytes and endothelial cells confirmed that irisin attenuated Dox-induced senescence. Taken together, these data provide evidence that exercise mitigates Dox-induced cardiotoxicity by suppressing cardiovascular senescence via a mechanism involving the exercise-induced myosin irisin, and that exercise is a potential intervention for preventing Dox-induced cardiotoxicity.

Alkaline ceramidase 2 (ACER2) catalyzes the hydrolysis of ceramides into sphingosine and free fatty acids, playing crucial roles in regulating various biological processes, including but not limited to cell proliferation, survival, and the DNA damage response. However, a pharmacological tool that regulates its catalytic and signaling functions remains to be developed. In this study, N-[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]dodecane-1-sulfonamide (KPB82) was identified as a potent and selective ACER2 inhibitor. In vitro enzymatic assays showed that KPB82 inhibited ACER2 with an IC 50 of 190 nM, while displaying minimal activity against acid and neutral ceramidases (IC 50 > 100 µM) and no significant inhibition of alkaline ceramidase 1 or alkaline ceramidase 3. Enzymatic kinetic studies revealed that KPB82 is a competitive inhibitor of ACER2. The three-dimensional structure of ACER2 was modeled in the AlphaFold3 server, revealing key Zn[2+]-coordinating histidine residues and a substrate-binding pocket. Molecular docking studies demonstrated that KPB82 binds ACER2 within this pocket, forming hydrogen bonds with the catalytically important amino residues, Asp93 and His215, and interacting with several hydrophobic residues. Lactate dehydrogenase release assays revealed that KPB82 significantly reduced cytotoxicity in HeLa cells overexpressing ACER2, as well as in HCT116 cells, RT4 cells, and human umbilical vein endothelial cells treated with the DNA-damaging agent doxorubicin. Lipidomic analysis showed that KPB82 inhibited sphingosine production in response to ACER2 overexpression or doxorubicin treatment. Collectively, these findings demonstrate that KPB82 is a potent and selective ACER2 inhibitor capable of suppressing ACER2-dependent biological processes and highlight its potential as a tool for studying ceramide metabolism and ACER2-mediated signaling pathways.

Surface engineering of bacterial microswimmers offers new opportunities for active cargo delivery by combining synthetic interfaces with intrinsic bacterial motility and environmental responsiveness. However, current strategies mainly focus on improving bacterial protection and cargo loading, whereas the effects of engineered interfaces on the biological functions required for active delivery remain poorly understood. Here, we developed a function-preserving biointerface engineering strategy by constructing thickness-tunable Fe[III]-tannic acid (Fe[III]TA) coatings with approximate thicknesses of 10-70 nm on Escherichia coli. The effects of interfacial shielding on bacterial viability, motility, and chemotactic responsiveness were systematically investigated. Increasing coating thickness enhanced bacterial resistance to antibiotics and enzymatic degradation but progressively impaired swimming performance and chemotactic migration due to physical restriction. Importantly, removal of the excessive coating restored bacterial motility, confirming that functional impairment resulted from reversible interface-induced constraints rather than bacterial damage. A coating approximately 20 nm thick provided the optimal functional balance, retaining 82.3% of the swimming velocity of bare bacteria and preserving glucose-responsive chemotaxis. The optimized bacterial microswimmer further enhanced doxorubicin delivery relative to the nonmotile control and, under near-infrared irradiation, markedly suppressed tumor growth in vivo without evident systemic toxicity. This study establishes function preservation as a key principle for biointerface engineering of bacterial carriers and provides a strategy for developing active delivery systems with maintained biological functionality.

Accurate monitoring of doxorubicin (DOX) is important for individualized chemotherapy, yet conventional fiber-optic surface plasmon resonance (SPR) sensors are often limited by large probe dimensions and temperature cross-sensitivity. In this paper, a compact fiber-tip microprobe that integrates SPR and Fabry-Perot interference (FPI) for synchronous detection of DOX concentration and temperature is reported. The microprobe is composed of a square frustum-similar structure, which is directly printed on the end face of a single-mode fiber by femtosecond laser-induced two-photon polymerization. By optimizing the structural parameters, SPR and FPI are simultaneously excited within the 24 μm-high microprobe. The sensing surface is further functionalized with the DOX-specific aptamer to enable selective molecular recognition. In the range of 0-100 μM DOX, the SPR and FPI channels exhibit sensitivities of 0.075 and 0.060 nm/μM, respectively, with corresponding limits of detection of 8.8 and 19.1 μM. Over 28-40 °C, the SPR and FPI temperature sensitivities are -0.66 and -0.61 nm/°C, respectively. A dual-parameter decoupling matrix enabled simultaneous determination of DOX concentration and temperature. The microprobe also showed satisfactory stability and selectivity, demonstrating its potential for miniaturized therapeutic drug monitoring.

Liposomal carriers are widely used for anticancer drug delivery due to their biocompatible nature in the biological milieu. Liposome-based drugs often face premature leakage, uncontrolled release, and insufficient control over long-term drug availability. Here, we present poly(lactic-co-glycolic acid) (PLGA)-coated mesoporous silica nanocarriers (PLGA-mSiO2, polysilomes) as an efficient and stable alternative to PEGylated liposomes. Such hybrid transporters are capable of efficiently encapsulating both hydrophilic [doxorubicin (DOX)] and hydrophobic [tamoxifen (TAM)] drugs. Investigation on drug loading, release kinetics, cellular uptake, and therapeutic response confirms the superior drug encapsulation and delivery of polysilomes efficiently. In liposomes, TAM was localized within the lipid bilayer, whereas DOX was actively loaded into the aqueous core through a transmembrane pH gradient. While this architecture enabled coloading, liposomes showed rapid drug release and pronounced cytotoxicity. In contrast, the core-shell structure of PLGA-mSiO2 polysilome carriers retained hydrophilic DOX within the mesoporous silica core and hydrophobic TAM within the PLGA shell. This compartmentalization ensures higher encapsulation efficiencies of both DOX (77.3%) and TAM (60.5%), with loading capacities of 59.3 and 50.4%, respectively. The PLGA-silica interface is a degradable diffusion barrier, enabling pH-responsive sustained release under acidic conditions. Moreover, PLGA-mSiO2 showed enhanced cellular uptake in MDA-MB-231 breast cancer cells and prolonged (up to 144 h) suppression of cell viability. These results present PLGA-coated mesoporous silica nanocarriers as a promising alternative to liposomal delivery by converting rapid drug release into sustained therapeutic activity.

Cancer remains one of the leading causes of mortality worldwide, highlighting the need for novel anticancer agents with improved efficacy and selectivity. In this study, a series of chalcone derivatives bearing phenylpiperazine, 2-fluorophenylpiperazine, and morpholine moieties (1a-g, 2a-g, and 3a-g) were designed, synthesized, and evaluated for their anticancer potential. The target compounds were synthesized via Claisen-Schmidt condensation under basic conditions and characterized by [1]H NMR, [13]C NMR, and elemental analysis. Their cytotoxic activities were assessed against PC-3, PANC-1, A549, and MCF-7 cancer cell lines using the MTT assay, with HEK-293 cells serving as a non-cancerous control. Most compounds exhibited notable antiproliferative activity and favorable selectivity compared with doxorubicin, cisplatin, and gemcitabine. Among the tested cell lines, A549 cells were the most sensitive. Compounds 2d, 2b, 2c, 2e, 2g, and 2a showed particularly potent activity against A549 cells, with IC50 values of 5.35 ± 0.08, 5.71 ± 0.09, 5.95 ± 0.09, 5.83 ± 0.09, 5.94 ± 0.09, and 5.96 ± 0.09 µM, respectively. Notably, 2c exhibited the highest selectivity toward A549 cells (SI = 3.26). SAR analysis indicated that the 2-fluorophenylpiperazine moiety enhanced anticancer activity, while halogen substitution generally improved potency and selectivity. Induced Fit Docking and Glide XP simulations supported these findings, suggesting that 2d and 2c achieve their activity through key hinge-region anchoring and isoform-specific interactions with PI3K-α and PI3K-γ. Overall, these findings identify fluorinated chalcone derivatives, particularly 2d, as promising leads for further anticancer drug development.

Primary thyroid diffuse large B-cell lymphoma (DLBCL) is a rare subset of primary extranodal DLBCL. Thus, there are limited evidence-based specific recommendations regarding its diagnosis and treatment. We present a case report of a patient with relapsed primary thyroid DLBCL, followed by a focused literature review covering key epidemiological, diagnostic, and therapeutic aspects. In 2017, a 74-year-old woman was diagnosed with primary thyroid non-GCB-type DLBCL (Ann Arbor IE, IPI 2) after presenting with dyspnoea, hoarseness, and cough. Treatment with R-CHOP and CNS prophylaxis achieved complete remission. Six years later, an isolated relapse occurred in the contralateral thyroid gland. The patient was treated with Pola-R-miniCHP (off-label), resulting in complete remission again. In the focused literature review core needle or surgical biopsy was found to be important for reliable histopathological characterization, while first-line treatment mainly consisted of rituximab-containing chemoimmunotherapy, occasionally combined with radiotherapy. Surgery was largely limited to diagnostic purposes. Reported 5-year overall survival rates ranged from 57% to 88%, whereas relapse or refractory disease and central nervous system involvement were rare. Registry-based studies, especially those focusing on primary extranodal DLBCL, are necessary to develop evidence-based treatment guidelines for these patients.