Lactoferrin (LF)-derived peptides (LDPs) are short cationic and amphipathic fragments generated primarily from the N-terminal lobe of LF through pepsin-mediated proteolytic processes. The best-characterized LDPs include lactoferricin (LFcin), lactoferrampin (LFampin), and LF1-11. In addition to these native peptides, a growing range of engineered LDPs has been developed by modifying the LFcin-derived RRWQWR motif through the incorporation of non-natural amino acids, cyclization, multimerization, and conjugation with chemotherapeutic agents. LDPs have garnered significant interest as potential anticancer peptides due to their ability to preferentially engage with the surfaces of malignant cells and initiate various tumor-suppressive mechanisms. This review article provides an overview of the principal classes of LDPs and elucidates how structural features influence membrane interaction, selectivity, intracellular targeting, apoptotic pathways, and immune modulation. It also discusses current mechanistic insights and examines the major challenges and opportunities for translating innovative LDPs into clinically useful cancer therapeutics.

Cardiovascular disease and cancer remain the leading causes of death worldwide. Although numerous cancer therapies have improved survival rates, they also increase the risk of cardiomyopathy, heart failure, and arrhythmias. These cardiovascular complications can limit treatment options and adversely affect the long-term quality of life of cancer survivors. CaV1.3, an L-type calcium channel encoded by CACNA1D, emerges as a central molecular mediator linking cardiovascular disease and cancer. It regulates calcium entry into cardiomyocytes and contributes to sinoatrial pacemaking and atrioventricular conduction. It also contributes to proliferation, migration, and therapy resistance in several cancers. Chemotherapy-induced oxidative stress, inflammatory signaling, hypoxia, and transcriptional changes can modulate the expression, gating, splicing, and trafficking of CaV1.3 channels. All these changes destabilize diastolic depolarization and impair conduction, thereby promoting arrhythmias in cancer patients. This review focuses on CaV1.3 biology in cardio-oncology, along with the mechanisms of chemotherapy-induced cardiotoxicity. It outlines the role of CaV1.3 as a key mediator linking cancer therapies to subsequent nodal dysfunction and increased arrhythmia susceptibility. It also expands on how patient-specific induced pluripotent stem cell-derived cardiomyocytes can model CaV1.3 dysregulation as well as support the development of targeted therapies. We propose that CaV1.3 represents a mechanistic bridge linking cancer therapy, calcium signaling, and cardiac electrophysiology, and that elucidating its pathophysiology may guide the design of targeted strategies in cardio-oncology.

Tumor microenvironment with high complexity and heterogeneity is one of the hallmarks of tumor and a key driver of treatment resistance. Conventional antitumor therapies, such as chemotherapy and radiotherapy, trigger tumor cell senescence through mechanisms involving DNA damage and oxidative stress. These senescent tumor cells, in turn, promote tumor malignancy via the senescence-associated secretory phenotype (SASP), thereby facilitating treatment resistance. Accumulating evidence indicates that, in addition to tumor cells, various microenvironmental components including endothelial cells, immune cells, and fibroblasts also undergo senescence in response to chemo- and radiotherapeutic stress. This prevalent therapy-induced microenvironmental senescence remodels the tumor microenvironment and fuels treatment resistance, highlighting its potential as a target for combination therapy. In this review, we outline the mechanisms underlying therapy-induced tumor cell senescence, with a particular emphasis on the mechanisms by which therapy-induced senescence of major non-tumoral components within tumor microenvironment mediates therapy resistance. Furthermore, we summarize the current therapeutic strategies targeting therapy-induced senescence, aiming to provide novel insights into the rational combination of senescence-targeted therapies with conventional radiotherapy and chemotherapy for tumor treatment.

Piperidone, a chemically versatile cyclic amine incorporating a ketone functional group, has emerged as a privileged scaffold in contemporary drug design owing to its synthetic adaptability and wide range of biological activities. This review provides a comprehensive overview of piperidone and piperidone-containing compounds that have been synthesized in laboratories, isolated from natural sources, or identified in marine organisms. Various synthetic strategies for constructing the piperidone scaffold are discussed, including multicomponent reactions, cycloadditions, organocatalytic methods, and microwave-assisted one-pot protocols. Piperidone derivatives exhibit a broad spectrum of biological activities, including antioxidant, anti-inflammatory, antimicrobial, antifungal, antiviral, neuroprotective, and, notably, anticancer effects across diverse cell lines. Interestingly, several derivatives exert their anticancer effects via more than one mechanism simultaneously, underscoring the importance of detailed structure-activity relationship (SAR) studies to delineate structural determinants responsible for specific modes of action. A deeper understanding of these mechanistic relationships could enable the rational design of novel piperidone-based molecules capable of targeting multiple pathways concurrently, thereby enhancing therapeutic efficacy. Moreover, investigating natural biosynthetic routes may facilitate scalable production of structurally complex piperidone derivatives, unlocking new opportunities in medicinal chemistry and drug development. Overall, this review highlights the significance of the piperidone scaffold as a key structural motif in rational drug design.

Glucose transporter 1 (GLUT1), the most extensively distributed member of the glucose transporter protein family, plays a pivotal role in regulating glucose metabolism and is indispensable for cellular growth, proliferation, and differentiation. Various metabolic disorders arise from the dysregulation of GLUT1 expression, which disrupts glucose homeostasis. The upregulation of GLUT1 has been identified in multiple cancer cells, facilitating tumor progression, metastasis, and resistance to treatment. Recent years have seen a surge in the discovery of GLUT1 inhibitors exhibiting improved selectivity and efficacy. Herein, we introduce the structure and biological function of GLUT1, GLUT1 related oncogenesis, and primarily focuses on recent advancements in the study of GLUT1 inhibitors over the last decade. Notably, this review is restricted to inhibitors that act through direct interaction with the GLUT1 protein, excluding agents that exert indirect effects via upstream signaling or metabolic regulation.

Tubulin inhibition remains a well-established strategy in anticancer therapy, mediated primarily through three binding sites on the α-β tubulin heterodimers: taxane, vinca, and colchicine binding site (CBS). Although several clinically approved drugs target the taxane and vinca sites, their efficacy is often compromised by multidrug resistance. In contrast, CBS remains an underexploited yet highly promising target, as no anticancer drug has been approved that specifically binds this site. Flavonoids, a diverse class of naturally occurring polyphenols, share structural features with colchicine and have emerged as potential CBS inhibitors with favourite safety profiles. Reported tubulin-inhibiting flavonoids encompass polymethoxylated (PMF), polyhydroxylated (PHF), and synthetic or semi-synthetic derivatives, with the most potent compounds exhibiting sub micromolar IC50 values. PMFs generally display stronger activity than PHFs, likely due to enhanced lipophilic interactions within the CBS pocket. Synthetic modifications extending beyond the traditional methoxy and hydroxy substituents have further improved potency. Computational modelling and X-ray crystallographic analyses consistently reveal that flavonoids and colchicine share a similar binding orientation at the CBS supporting their potential as scaffolds for rational anticancer drug design. This review highlights the biochemical, structural, and mechanistic features of flavonoids targeting CBS and discusses their promise as leads for novel CBS inhibitors.

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide, despite significant advances in early detection and treatment. Conventional chemotherapeutic agents often face limitations such as drug resistance, off-target toxicity, and poor patient adherence. These challenges have highlighted the need for safer, more effective alternatives. Naturally derived compounds, especially flavonoids such as quercetin, have recently attracted attention for their ability to modulate key cancer pathways with minimal side effects. This review critically examines natural quercetin and its metabolites in the context of breast cancer prevention and treatment, focusing on their molecular targets and pharmacodynamic effects. To address issues such as poor bioavailability and rapid metabolism, we also discuss the design and synthesis of quercetin derivatives that exhibit improved stability, solubility, and targeted delivery. Additionally, the review highlights emerging quercetin-based nanomaterials designed to enhance therapeutic precision. This review offers a comprehensive overview of the development of quercetin-based therapies, outlining current progress, identifying translational hurdles, and proposing future directions for the development of optimized, targeted, and clinically viable quercetin formulations for breast cancer treatment.

Piperazine has become essential for designing anticancer drugs because of its basicity, conformational flexibility, and capacity to serve as a solubilizing agent and molecular linker between hybrid pharmacophores. Researchers have found piperazine to function as a medicinal chemistry component that helps develop bioactive scaffolds through its capacity to control solubility, linker design, and target binding properties. The review presents a comprehensive assessment of piperazine-based anticancer drug research published between 2015 and 2025 through its evaluation of clinically relevant medicinal chemistry findings. The literature is organized based on piperazine's three main functional roles, which include its use as a linker and solubilizing/basic motif and direct target-recognition element. The study examines major cancer types through scaffold-based structure-activity relationship (SAR) analysis, which includes breast cancer, liver cancer, colon cancer, cervical cancer, prostate cancer, brain cancer, and leukemia models. The research demonstrated that various derivatives achieved IC₅₀ values in the low-nanomolar to low-micromolar range in MCF-7, HepG2, and HCT-116, HeLa, PC-3, and K562 cell lines. Researchers have demonstrated how protonatable piperazine nitrogens improve aqueous solubility and formulation development, and interactions of enzyme and kinase active sites with acidic residues, which results in better binding strength and selectivity. The review presents major translational obstacles, which include excessive dependence on 2D in vitro studies, insufficient in vivo and ADME/PK information, and limited progress in clinical applications. The research studies the development of clinically usable piperazine-based anticancer drugs through novel methods, which include green chemistry, click chemistry, molecular docking, and QSAR-focused design.

Beilschmiedia (the family Lauraceae) is a large tropical genus containing species traditionally used to treat rheumatism, tumors, malaria, infections, and others. Despite extensive ethnomedicinal applications, a comprehensive evaluation of its phytochemistry and pharmacology remains limited. This review aims to consolidate current knowledge on the phytochemical diversity, biosynthetic and synthetic pathways, pharmacological potential, and chemical modifications of Beilschmiedia species. Relevant studies were retrieved from PubMed, Scopus, Web of Science, and Google Scholar up to September 2025 using "Beilschmiedia" as the main keyword. Eligible publications included original reports on phytochemical isolation, structure elucidation, biosynthetic studies, synthetic modification, and pharmacological evaluation, whereas botanical identifications were excluded. Over 240 compounds were characterized from 30 Beilschmiedia species, encompassing tetracyclic polyketides, alkaloids, terpenoids, phytosterols, lignans, neolignans, flavonoids, alkamides, and others. Endiandric acids and cyclobutane/oxetane-type neolignans, possessing unique skeletons, could be chemotaxonomic significance. Pharmacological studies have revealed diverse activities, such as cytotoxic, antimicrobial, antimalarial, antioxidant, anti-inflammatory, antidiabetic, and cholinesterase-inhibitory activities. Advances in biosynthesis, total synthesis, and semi-synthetic modification have facilitated the exploration of structure-activity relationships. Beilschmiedia represents a valuable reservoir of chemically novel and biologically active compounds. Future research should expand phytochemical surveys to underexplored species, integrate metabolomic and genomic approaches, and conduct advanced pharmacological studies, including in vivo validation and formulation development.

Pyridine is a common nitrogen-containing heteroaromatic motif in antitumor medicinal chemistry, but its design value is highly context dependent. Here, we synthesize structure-oriented medicinal chemistry principles that govern the use of pyridine-related motifs in antitumor drug design. We discuss pyridine-containing antitumor agents with emphasis on target recognition, scaffold organization, structure-activity relationship (SAR), drug metabolism and pharmacokinetics (DMPK), and absorption, distribution, metabolism, excretion, and toxicity (ADMET) liabilities. Representative approved drugs, antibody-drug conjugate (ADC) payloads, targeted degraders, and polypyridyl metal complexes are used to illustrate how pyridine-related motifs can support binding, property tuning, and modality adaptation. By grouping representative compounds according to the medicinal chemistry function of their pyridine-related motifs, this review provides a practical framework for future scaffold design. Overall, pyridine should not be viewed as a universally beneficial privileged scaffold; it is better treated as a context-dependent design module that requires validation through integrated structural, SAR, ADMET, and translational evidence.

Curcuma longa (turmeric) is a well-known medicinal plant that is rich in bioactive phytochemicals, among which curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) are the principal constituents responsible for diverse pharmacological activities, ranging from antibacterial to anticancer. Despite its multifaceted therapeutic potential and clinical safety, the unfavorable pharmaceutical properties are limiting its clinical efficacy and hence are not able to attain the drug standard. Interestingly, this review provides a comprehensive overview of the complete phytochemical constituents of C. longa, and on the other hand, recent advancements (2020-2025) in the design and development of curcumin-based hybrid molecules aimed at overcoming the aforementioned limitations. Literature was systematically analyzed, focusing on structural modifications of curcuminoids, including functional group transformations, heterocycle incorporation, and monocarbonyl scaffold simplification to exploit these strategies' significance on pharmacokinetic properties, metabolic stability, and anticancer activity. In particular, monocarbonyl curcumin-piperidone hybrids exhibit improved cytotoxicity, redox modulation, and multitarget mechanisms compared with curcumin and its other hybrids. Overall, curcumin hybridization represents a promising approach that bridges traditional herbal knowledge with modern drug discovery, offering valuable candidates for the development of effective anticancer therapeutics.

CDK4/6 inhibitors combined with endocrine therapy (ET) has significantly improved progression-free (PFS) and overall survival (OS) in patients with hormone receptor-positive (HR+), HER2-negative breast cancer, however, most patients ultimately develop acquired resistance and experience disease progression. Historically, this transition marked the point at which chemotherapy was initiated; however, advances in molecular profiling and drug development have fundamentally altered this paradigm.Resistance to endocrine therapy is mediated by distinct and therapeutically actionable mechanisms, most notably ESR1 mutations, activation of the PI3K/AKT/mTOR signaling pathway, and cell-cycle deregulation. These insights have led to the development of a new generation of targeted endocrine therapies that restore or prolong endocrine sensitivity. Oral selective estrogen receptor degraders (SERDs), particularly elacestrant and imlunestrant, have demonstrated clinically meaningful efficacy in patients with ESR1-mutant tumors progressing after CDK4/6 inhibitors. Additionally, targeted inhibitors of the PI3K and AKT pathways, such as alpelisib and capivasertib, when combined with appropriate endocrine backbones, have been shown to overcome resistance mechanisms.The emergence of circulating tumor DNA (ctDNA) testing has further refined therapeutic decision-making by enabling real-time detection of resistance mutations and guiding directed treatment selection. Several prospective trials have demonstrated that molecularly guided switching of endocrine therapy can delay clinical progression and extend disease control, highlighting a shift toward precision-based, adaptive strategies.Collectively, these advances support a new treatment paradigm in which endocrine-based combinations remain the preferred approach after progression, delaying the need for chemotherapy while maintaining efficacy and quality of life. This review summarizes the biology of endocrine resistance, evaluates current targeted endocrine therapies, and provides a practical framework for biomarker-driven sequencing in patients with HR+/HER2- advanced breast cancer following progression on prior endocrine therapy.

Cisplatin resistance in ovarian cancer, particularly in ovarian clear cell carcinoma, involves intricate mechanisms related to oxidative stress, deoxyribonucleic acid repair, and cell cycle. Resistance in ovarian clear cell carcinoma is associated with genes, such as pyruvate dehydrogenase kinase-2 and hepatocyte nuclear factor 1 beta, which enhance glycolysis and reduce reactive oxygen species that would normally facilitate cisplatin induced deoxyribonucleic acid damage. Additionally, nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 play pivotal roles in regulating reactive oxygen species levels, thereby safeguarding ovarian clear cell carcinoma cells from oxidative damage. The postsynaptic density protein 95/discs large/zona occludens-1 (PDZ)-binding motif-angiopoietin-like 4 nicotinamide adenine dinucleotide phosphate oxidase-2 axis plays a crucial role in modulating ferroptosis, presenting potential therapeutic targets. A deeper understanding of these mechanisms offers promising strategies to overcome cisplatin resistance, particularly in ovarian clear cell carcinoma. These insights could pave the way for targetted therapies aimed at improving ovarian cancer outcomes, especially for ovarian clear cell carcinoma subtypes.

Lung cancer is typically a cancer of the elderly, with a median age at diagnosis of 71, and more than one third of the people diagnosed with lung cancer are over 75 years old. Immune checkpoint inhibitors (ICIs) have revolutionised the treatment of cancers, including lung cancer. ICIs targeting the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis, administered in the neoadjuvant setting, the adjuvant setting, or both, are currently the standard of care for resectable non-small-cell lung cancer (NSCLC) worldwide. These ICIs are commonly used in combination with platinum-based chemotherapy and have shown superior efficacy in patients eligible for curative surgery. The concept of immunosenescence, which refers to age-related changes in the immune system - particularly a decline in the efficiency of T-cell mediated responses - raises concerns about the benefits of ICIs in the elderly population.

This article reviews pharmacological strategies targeting key metabolic pathways in cancer cells and highlights their inherent limitations, including metabolic plasticity and lack of selectivity. It is proposed that these vulnerabilities can be addressed through a global redox-based approach using high-dose vitamin C. Evidence suggests that the anticancer activity of vitamin C is mediated by its oxidation to dehydroascorbic acid (DHA). Although DHA cannot be administered directly due to its instability, it can be generated in situ within the circulatory system. Once taken up by cancer cells, DHA perturbs multiple redox-sensitive processes, leading to depletion of NADPH and collapse of cellular redox homeostasis. We present a mechanistic framework outlining how controlled generation of DHA may enable a more robust and clinically effective anticancer strategy.

Metformin is a cornerstone medication for type 2 diabetes and exhibits anti-tumor activities. Previous studies have demonstrated that metformin suppresses tumor progression by regulating multiple signaling pathways, including the AMPK, PI3K/AKT/mTOR, and JNK pathways. However, most previous studies have focused on its direct effects on tumor cells, with limited attention to its effects in the TME. The TME constitutes a multifaceted ecosystem that drives tumor development and therapeutic resistance via physical barrier formation, immune evasion, and abnormal angiogenesis. In this review, we systematically summarize the impact and underlying regulatory mechanisms of metformin on distinct components of the TME. In addition, we discuss the individual and combined roles of metformin in immunity and inflammation, as well as vascular, matrix, and metabolic regulation. By elucidating the mechanisms of metformin-mediated TME reprogramming, we aim to provide new perspectives for understanding its anti-tumor effects and facilitating its clinical translation in cancer therapy.

Immune checkpoint inhibitors (ICIs), comprising anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death protein 1 (PD-1), and anti-programmed death-ligand 1 (PD-L1), have transformed melanoma therapy, yet the tumour microenvironment (TME), the pivotal biological interface where therapeutic efficacy, resistance, and toxicity are determined, remains incompletely characterized. This dual systematic review and meta-analysis (PROSPERO: CRD420261374242) followed PRISMA 2020 and included 58 preclinical (B16F10/C57BL/6; 46 quantitative) and 44 clinical studies (19 quantitative) to calculate pooled standardized mean differences (SMDs) for six intratumoral TME parameters. Checkpoint blockade consistently shifted the TME toward an immune-activated state, an effect that remained robust in sensitivity analyses despite substantial heterogeneity (I-squared heterogeneity statistic (I2) = 68-88%). Preclinically, ICIs significantly increased CD8+ T-cell infiltration (SMD = 1.45, p < 0.001), interferon-gamma (IFN-γ) (SMD = 1.78, p < 0.001), CD8/regulatory T-cell (Treg) ratio (SMD = 0.91, p = 0.005), and apoptosis (SMD = 3.54, p < 0.001) and reduced PD-L1 (SMD = -0.88, p = 0.004) and Ki-67 (SMD = -1.43, p = 0.028). Clinically, CD8+ infiltration and PD-L1 both increased (SMD = 0.72, p < 0.001; SMD = 0.67, p = 0.001), contrasting with the preclinical PD-L1 decrease. Meta-regression demonstrated superior anti-PD-L1 efficacy over CTLA-4 for effector parameters: IFN-γ +3.59 (p = 0.009), CD8/Treg +10.69 (p = 0.003), apoptosis +9.76 (p = 0.004), and Ki-67 -6.28 (p = 0.040). These findings establish the TME as a critical determinant of ICI outcomes, indicate that PD-L1 amplifies effector functions in the B16F10 model, and highlight translational gaps in TME reprogramming.

Leukemia represents a heterogeneous and refractory hematological malignancy, with current clinical therapies, including conventional chemotherapy, targeted therapy, and hematopoietic stem cell transplantation, still limited by drug resistance, off-target toxicity, and poor efficacy against high-risk subtypes. Indole/azaindole is a privileged heterocyclic scaffold in medicinal chemistry with versatile structural modification potential and inherent antileukemic bioactivity. Rational hybridization of indole/azaindole with diverse pharmacophores has become a core strategy for developing novel antileukemic agents, thereby enabling synergistic efficacy, reversal of drug resistance, and reduced toxicity. This review systematically summarizes the research progress of indole-based hybrids and closely related indole bioisosteres (azaindole hybrids) with antileukemic activity from 2021 to the present. Distinct from previous descriptive reviews, we stratified all candidate compounds by evidence hierarchy: in vitro antiproliferative activity, molecular mechanistic validation, and in vivo preclinical efficacy. This work focuses on structure-activity relationships (SARs), multi-target mechanisms, and preclinical pharmacological characteristics of indole- and azaindole-based antileukemic hybrids, aiming to provide targeted guidance for the rational design and clinical translation of novel indole- and azaindole-based antileukemic drugs.

Ginsenoside Rg3, a rare protopanaxadiol-type saponin enriched during the heat processing of Panax ginseng, has attracted increasing attention as a multitarget anticancer agent. This systematic review examines the anticancer potential of Rg3 through comprehensive searches of the PubMed and Web of Science databases, with a focus on peer-reviewed preclinical and clinical studies. The therapeutic efficacy of Rg3 is critically influenced by its stereochemical configuration, concentration-dependent bidirectional regulation, and pharmacokinetic constraints, including poor oral bioavailability, rapid clearance, and gut microbiota-mediated metabolism. Nanocarrier-based and targeted delivery systems have substantially improved its pharmacokinetic profile and tumor accumulation, supporting its further development for anticancer applications. Within this pharmacological context, Rg3 exhibits broad-spectrum anticancer activity across multiple solid tumors, including hepatocellular carcinoma, melanoma, lung, ovarian, breast, colon, gastric, and prostate cancers, as well as osteosarcoma, renal cancer, lung adenocarcinoma, glioblastoma, gallbladder, nasopharyngeal, cervical, and pancreatic cancers, and the hematological malignancy multiple myeloma. Mechanistically, Rg3 suppresses cancer progression through coordinated regulation of proliferation, apoptosis, autophagy, ferroptosis, angiogenesis, epithelial-mesenchymal transition, cancer stemness, immune evasion, and redox homeostasis, primarily involving the PI3K/AKT/mTOR, NF-[Formula: see text]B, MAPK, Wnt/[Formula: see text]-catenin, EGFR, and p53 pathways. These effects reflect transferable network-level mechanisms rather than tumor type-restricted actions. Moreover, Rg3 demonstrates synergistic effects with chemotherapy, radiotherapy, targeted therapy, and immunotherapy, while reversing drug resistance and attenuating treatment-related toxicity in multiple cancer models and clinical settings. Overall, this review systematically integrates current evidence on the pharmacokinetics, anticancer spectrum, molecular mechanisms, synergistic combinations, immunomodulatory effects, and clinical applications of Rg3, providing a concise framework for the rational development of Rg3-based combination strategies in precision cancer therapy.

With the increasing global burden of cancer, traditional chemotherapy is limited by issues such as high toxicity and poor targeting, making the development of new therapeutic strategies an urgent priority. As natural bioactive macromolecules, herbal polysaccharides have become a hotspot in antitumor research due to their multi‑target effects, low toxicity, and excellent biocompatibility. The present review summarizes recent advances in the mechanisms of plant polysaccharides in antitumor activity and their applications in drug delivery systems. It highlights their synergistic antitumor effects through multiple pathways, including regulation of the immune microenvironment, induction of programmed cell death, modulation of the microbiota‑immune axis, and inhibition of angiogenesis and metastasis. These compounds significantly enhance the efficacy of chemotherapy and immunotherapy while reversing drug resistance. Novel formulations such as polysaccharide‑based nano‑delivery systems, selenium‑modified complexes and gel platforms have further improved drug targeting, stability, and immunomodulatory efficacy, providing a solid theoretical foundation and innovative directions for integrated traditional Chinese and Western medicine in cancer treatment.