Extravasation of cytostatic drugs is a rare but potentially devastating complication of chemotherapy in children, leading to severe pain, tissue necrosis, functional impairment, and cosmetic deformities. Despite its importance, management protocols remain inconsistent. This paper presents structured instructions to support rapid recognition, intervention, and prevention of cytostatic extravasation in paediatric patients, aiming to reduce morbidity and optimise outcomes. The guidance was developed from published recommendations, systematic reviews, and institutional experience, and it provides a stepwise algorithm for immediate management: stopping infusion, retaining intravenous access for aspiration, marking and documenting the affected site, and performing clinical assessment. Specific measures include aspiration techniques for peripheral and central lines, administration of antidotes such as dexrazoxane, dimethyl sulfoxide, or hyaluronidase, and application of cold or warm compresses depending on the cytostatic agent. Preventive strategies emphasise correct vessel selection, careful cannula monitoring, and strict adherence to administration procedures. For advanced necrosis or refractory injury, surgical approaches - such as early wash-out, liposuction, excision with negative- pressure wound therapy, skin grafting, and complex reconstructions - are outlined. The proposed framework integrates available evidence and expert consensus into a practical and user-friendly protocol. Its implementation may facilitate early detection, minimise the risk of severe complications, and promote standardised paediatric oncology care. In conclusion, cytostatic extravasation in children requires prompt, structured, interdisciplinary management. Early use of specific antidotes and supportive measures can prevent irreversible damage, while preventive strategies and vigilant monitoring remain crucial. Surgical interventions should be reserved for severe, non-responsive cases.

The clinical utility of doxorubicin (DOX) is severely limited by dose-dependent cardiotoxicity, for which effective interventions remain scarce. Huangqi Guizhi Wuwu Decoction (HGWD) shows promising cardioprotective potential, but its mechanisms against DOX-induced cardiotoxicity (DIC) remain unexplored. This study explored the molecular mechanisms using an integrated metabolomics and transcriptomics approach. We identified 57 compounds in HGWD by liquid chromatography ion trap time-of-flight mass spectrometry (LC-IT-TOF/MS), and quantified five representative compounds for standardization. Mice were randomized into six groups: control, DOX (10 mg/kg × 2), DOX + low-dose HGWD (7 g/kg/d), DOX + high-dose HGWD (14 g/kg/d), DOX + dexrazoxane (100 mg/kg × 2), and HGWD (14 g/kg/d) alone. HGWD effectively alleviated cardiac dysfunction and reduced serum injury markers, with the high-dose group demonstrating efficacy comparable to the positive control drug, dexrazoxane. Subsequently, multi-omics profiling was performed on heart tissues from the control, DOX, and DOX + high-dose HGWD groups. Metabolomics identified 31 differential metabolites, highlighting energy metabolism restoration (e.g., acylcarnitines, citric acid) and inflammatory mediator modulation (e.g., arachidonic acid). Transcriptomics uncovered 37 genes enriched in innate immunity (e.g., Irf7, Isg15) and apoptosis (e.g., Bax, Cdkn1a). Network analysis constructed a core regulatory module, pinpointing CDKN1A as a potential mediator. Validation experiments confirmed that HGWD suppressed DOX-induced CDKN1A upregulation in mouse hearts. Furthermore, in H9c2 cells, HGWD mitigated DOX-induced apoptosis and inflammation, exhibiting cytoprotection comparable to pifithrin-α, a specific p53 inhibitor. In summary, HGWD protects against DIC by modulating a multi-target network and the suppression of CDKN1A represents a key underlying mechanism.

Anthracyclines remain among the most effective cytotoxic drugs, but their cumulative cardiotoxicity limits dosing and threatens survivors with heart failure. The discovery that doxorubicin kills cardiomyocytes substantially through ferroptosis-an iron-dependent, lipid-peroxidation-driven cell death-has reframed the mechanism and identified a defined target, and the field has rapidly populated with iron chelators, radical-trapping inhibitors and Nrf2/GPX4-activating natural products reported to protect the heart. This review argues that the prevailing enthusiasm is mismatched to the biology in two respects. First, doxorubicin engages several regulated cell-death programmes at once, and ferroptosis operates within a multilayered defence network (GPX4, the FSP1-coenzyme-Q10 axis, mitochondrial DHODH and GTP-cyclohydrolase-1/tetrahydrobiopterin); blocking one node redistributes death and helps explain why ferroptosis inhibitors have failed, and even worsened outcomes, in some doxorubicin models. Second, and more fundamentally, ferroptosis is tumour-suppressive and contributes to the anticancer efficacy of chemotherapy, radiotherapy and immunotherapy, so systemic ferroptosis inhibition to protect the heart risks shielding the tumour-a paradox the cardioprotection literature largely ignores. The single approved agent, dexrazoxane, is acceptable precisely because evidence indicates it spares antitumour efficacy. The path to translatable cardioprotection therefore runs not through broad ferroptosis blockade but through cardiac- and mitochondria-selective, appropriately timed reinforcement of iron handling and lipid-peroxidation defence, validated against hard cardiac endpoints and preserved tumour control. Ferroptosis is a genuine and central mechanism of anthracycline cardiotoxicity; converting that mechanism into safe therapy is a harder problem than the current literature acknowledges.

Doxorubicin (DOX), a widely used chemotherapeutic, is significantly limited by dose-dependent cardiotoxicity characterized by oxidative stress, mitochondrial dysfunction, and ferroptosis. Despite decades of research, dexrazoxane (DXZ) remains the only approved cardioprotectant, yet its clinical utility is constrained by potential reduction in efficacy and systemic toxicity. Effective alternatives are therefore urgently needed. Through high-throughput screening of a 960-compound natural product library, we identified arctigenin (ATG), a major bioactive compound from the Asian medicinal plant Arctium lappa L., as a promising cardioprotective candidate against DOX-induced cardiotoxicity (DIC). Both in vitro and in vivo studies demonstrated that ATG significantly attenuated DOX-induced cell death, reduced reactive oxygen species (ROS) accumulation, inhibited ferroptosis, preserved mitochondrial function, and improved cardiac function and myocardial structural integrity in mice. Mechanistically, ATG activated the nuclear factor erythroid 2-related factor 2 (NRF2)-antioxidant response element (ARE) pathway by binding to the serine 602 (S602) residue of Kelch-like ECH-associated protein 1 (KEAP1), which competitively inhibited the KEAP1-NRF2 interaction. This binding facilitated the dissociation of NRF2 from KEAP1, resulting in reduced NRF2 ubiquitination, increased nuclear accumulation of NRF2, and enhanced transcription of downstream target genes. Collectively, our results identify ATG as a novel NRF2 activator that alleviates DIC through suppression oxidative stress and ferroptosis by directly targeting the KEAP1-NRF2-ARE axis.

Doxorubicin (DOX), a frontline chemotherapeutic agent, is severely limited by reactive oxygen species (ROS) overload-mediated cardiotoxicity involving multiple programmed cell death pathways, with pyroptosis validated as one major mechanism, whereas conventional cardioprotective interventions may compromise antitumor efficacy. Here, we report a selectively redox-responsive approach based on self-crosslinked lipoic acid nanoparticles (LANPs) that enables bidirectional pyroptosis regulation in cardiac vs. tumor tissues, achieving concurrent cardioprotection and antitumor sensitization during DOX therapy. In cardiomyocytes, LANPs degrade into the lipoic acid (LA)/dihydrolipoic acid (DHLA) pair, which exerts anti-oxidant activity to scavenge excessive ROS, thereby mitigating oxidative stress-associated pyroptosis and subsequent cardiac injury. In cancer cells with a relatively high reducing environment, LANP degradation predominantly yields DHLA, which promotes ROS accumulation, thereby enhancing pyroptosis-associated antitumor efficacy. In female BALB/c mouse models, LANPs afford cardioprotection comparable to dexrazoxane (DEX), the only clinically approved cardioprotective agent against DOX, while additionally alleviating systemic toxicity, particularly bone marrow suppression, an advantage not afforded by DEX. As expected, LANPs not only preserve but also potentiate DOX-induced antitumor efficacy. This study establishes LANPs as a promising adjuvant strategy for expanding the scope of chemotherapeutic applications beyond DOX.

The role of DNA topoisomerase II beta (TOP2B) in cardiomyocyte differentiation is poorly understood. To address this, human induced pluripotent stem cells (hiPSC) were differentiated into cardiomyocytes (CM) that were wild type (WT) or contained a genomic deletion of Topoisomerase 2B (BKO). Both WT and BKO hiPSC could be induced to differentiate into sheets of beating cardiomyocytes. BKO hiPSC take slightly longer to differentiate into sheets of beating CM than WT iPSC. RNA was prepared from both undifferentiated and differentiated WT and BKO hiPSC. RNA-seq was used to examine gene expression changes when the WT and BKO hiPSC were differentiated into CM. Gene expression changes following differentiation of BKO cells were largely similar to those in WT cells. In addition, the differentiated WT CM were treated with dexrazoxane (ICRF-187), a TOP2 catalytic inhibitor that targets both TOP2A and TOP2B, or topobexin, a new TOP2B selective catalytic inhibitor. Topobexin inhibition partially phenocopied a TOP2B deletion and thereby providing an alternative to TOP2B gene knockout in many cell lines. In future, hiPSC derived CM with and without TOP2B and inhibition by topobexin ex vivo CM could be used to study anthracycline-induced cardiotoxicity and to screen for cardioprotectants.

Microsporidia are diverse intracellular fungal parasites of humans and agriculturally important animals. Several inhibitors have been characterized, but their microsporidian targets and the mechanisms of resistance evolution remain unknown. Using C. elegans and its natural microsporidian parasite Nematocida parisii, we serially passaged infected animals under increasing inhibitor concentrations, generating independent N. parisii strains resistant to albendazole or dexrazoxane. The albendazole-resistant strains all contained either heterozygous or homozygous mutations in beta-tubulin, with several strains containing beta-tubulin variants that have been observed in other albendazole-resistant organisms. Strains containing homozygous variants are resistant to several albendazole analogs, whereas the heterozygous variant-containing strains are only resistant to albendazole. Several of the albendazole-resistant strains also contain mutations in alpha-tubulin. The dexrazoxane-resistant strains all contain heterozygous mutations in topoisomerase II, and several of these mutations occur in the binding site of this inhibitor. By mapping heterozygosity of the resistant strains across the N. parisii genome, we observed loss of heterozygosity spanning the beta-tubulin locus in the albendazole-resistant strains containing homozygous beta-tubulin variants. Our study demonstrates the utility of forward genetics for identifying microsporidian drug targets. We also find that drug resistance arises through de novo heterozygous mutations that can subsequently become homozygous, likely via mitotic recombination.