Platinum-based drugs are widely used in chemotherapy for various types of cancer and are considered crucial. Tetravalent platinum (Pt(IV)) compounds have gained significant attention and have been extensively researched among these drugs. Traditionally, Pt(IV) compounds are reduced to divalent platinum (Pt(II)) after entering cells, causing DNA lesions and exhibiting their anti-tumor effect. However, the available evidence indicates that some Pt(IV) derivatives may differ from the traditional mechanism and exert their anti-tumor effect through their overall structure. This review primarily focuses on the existing literature regarding targeted Pt(II) and Pt(IV) compounds, with a specific emphasis on their in vivo mode of action and the properties of reduction release in multifunctional Pt(IV) compounds. This review provides a comprehensive summary of the design and synthesis strategies employed for Pt(II) derivatives that selectively target various enzymes (glucose receptor, folate, telomerase, etc.) or substances (mitochondria, oleic acid, etc.). Furthermore, it thoroughly examines and summarizes the rational design, anti-tumor mechanism of action, and reductive release capacity of novel multifunctional Pt(IV) compounds, such as those targeting p53-MDM2, COX-2, lipid metabolism, dual drugs, and drug delivery systems. Finally, this review aims to provide theoretical support for the rational design and development of new targeted Pt(IV) compounds.

Antibody–drug conjugates (ADCs) have become an important class of targeted anticancer therapeutics by integrating the tumor selectivity of monoclonal antibodies with the potent cytotoxicity of small-molecule payloads through rational linker design. This review summarizes the structural fundamentals of ADCs, including antibodies, linkers, and payloads, and describes their coordinated mechanism of action. We trace the evolutionary trajectory of ADCs across three generations, highlighting key breakthroughs, limitations, and representative agents for each era. Furthermore, we elaborate on cleavage mechanisms of linkers (cleavable and non-cleavable). We also categorize and discuss cytotoxic payloads, covering traditional microtubule-disrupting agents, DNA-damaging agents, and novel mechanism-based payloads, along with their modification strategies and preclinical/clinical performance. Finally, we discuss representative and clinically influential ADC designs, with emphasis on the relationships among antibody, linker, and payload.

In the field of tumor treatment, drug resistance remains a significant challenge requiring urgent intervention. Recent developments in cell death research have highlighted cuproptosis, a mechanism of cell death induced by copper, as a promising avenue for understanding tumor biology and addressing drug resistance. Cuproptosis is initiated by the dysregulation of copper homeostasis, which in turn triggers mitochondrial metabolic disruptions and induces proteotoxic stress. This process specifically entails the accumulation of lipoylated proteins and the depletion of iron-sulfur cluster proteins within the context of the tricarboxylic acid cycle. Simultaneously, it is accompanied by the activation of distinct signaling pathways that collectively lead to cell death. Emerging evidence highlights the critical role of cuproptosis in addressing tumor drug resistance. However, the core molecular mechanisms of cuproptosis, regulation of the tumor microenvironment, and clinical translation pathways still require further exploration. This review examines the intersection of cuproptosis and tumor drug resistance, detailing the essential roles of cuproptosis-related genes and exploring the therapeutic potential of copper ionophores, chelators, and nanodelivery systems. These mechanisms offer promise for overcoming resistance and advancing tumor precision medicine. By elucidating the molecular mechanisms underlying cuproptosis, this study aims to identify novel therapeutic strategies and targets, thereby paving the way for the development of innovative anti-cancer drugs.

Therapeutic resistance remains a major obstacle to durable cancer control, with functional reprogramming of the DNA damage response (DDR) network playing a central role. The poly(ADP-ribose) polymerase (PARP) family, particularly PARP1 and PARP2, is crucial for maintaining genomic integrity. By exploiting synthetic lethality, PARP inhibitors (PARPi) selectively target tumors with homologous recombination deficiency (HRD) and are integral to precision therapy in ovarian, breast, and prostate cancers. However, over 40% of patients with BRCA1/2 alterations develop resistance, and patient eligibility remains limited by the low prevalence of HRD mutations. In this review, we summarize the molecular mechanisms of PARPi action, resistance pathways, and emerging combination strategies. PARPi resistance arises through HR restoration (e.g., BRCA1/2 reversion mutations), replication fork protection, RAD51-mediated strand invasion, and metabolic reprogramming. Combination therapies, integrating PARPi with histone deacetylase inhibitors, cyclin-dependent kinase inhibitors, immune checkpoint blockade, or radiation, enhance efficacy by converging on DNA repair pathways and the tumor immune microenvironment. A deeper understanding of coordinated DDR regulation and rationally designed combination regimens will be essential for overcoming PARPi resistance and advancing adaptive, precision-based therapeutic strategies.

Parkinson’s disease (PD), a debilitating neurodegenerative disorder, is primarily characterized by motor impairments and concurrent gastrointestinal disturbances. Increasing evidence has highlighted the critical role of the microbiota–gut–brain axis (MGBA) in the pathogenesis of PD. This study investigated the neuroprotective potential of sodium hyaluronate (SH) in a mouse model of PD and its underlying mechanisms via the MGBA. In the oral pre-treatment study, three doses (7.5, 15, and 30 mg/kg/day) were evaluated. The results showed that the high dose (SH-H, 30 mg/kg/day) significantly ameliorated motor disorders and gastrointestinal functional disorders. Therefore, SH-H was selected for subsequent mechanistic investigations. Mechanistically, SH-H restored gut microbiota homeostasis, increased fecal short-chain fatty acid (SCFA) levels, and improved the integrity of the intestinal and blood–brain barrier (BBB). Thus, SH reduced the transfer of lipopolysaccharide (LPS) from the intestine to serum and the substantia nigra (SN), suppressing activation of the LPS-TLR4/MyD88/NF-κB signaling pathway. These effects alleviated neuroinflammation, protected dopaminergic neurons, and reduced the aggregation of α-synuclein (α-syn). In summary, SH attenuated PD-related pathological changes by restoring gut microbiota homeostasis and modulating the MGBA, suggesting that SH may represent a potential therapeutic strategy for PD.