Lanyang Gao

Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism–modification axis for cancer therapy.

The cover image is based on the article Nanoemulsion‐based transdermal delivery of third‐generation steroidal and non‐steroidal aromatase inhibitors in preclinical models by Lanyang Gao et al., https://doi.org/10.1111/cpr.13753. image

Aromatase inhibitors are effective in treating hormone receptor‐positive breast cancer, particularly in postmenopausal women. However, the challenges of inconsistent dissolution, variable absorption and side effects with oral administration persist. To address these issues, transdermal delivery has emerged as a viable alternative. In our study, we have developed nanoemulsion‐based transdermal creams containing third‐generation aromatase inhibitors Exemestane (EXE) or Letrozole (LE) and evaluated their toxicity, anti‐tumour effects and androgenic potency using preclinical models including Bama minipigs, DMBA‐induced breast cancer rats and orchidectomized male rats. The results of our study are significant, suggesting that both creams effectively penetrated the skin, demonstrating an impressive anti‐breast cancer effect. Importantly, EXE cream had no organ toxicity at the tested dose, providing a reassuring safety profile for its use. In contrast, LE cream displayed reversible toxicity from drug molecule itself in animals at the given dose, dissipating after 3 weeks of withdrawal and recovery. This study establishes a solid foundation for the safe clinical use of third‐generation aromatase inhibitors. It highlights transdermal creams as a promising drug delivery carrier for administering them.

Lung cancer is the second most commonly diagnosed cancer and a leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the most prevalent type. Over 70% of lung cancer patients require radiotherapy (RT), which operates through direct and indirect mechanisms to treat cancer. However, RT can damage healthy tissues and encounter radiological resistance, making it crucial to enhance its precision to optimize treatment outcomes, minimize side effects, and overcome radioresistance. Integrating nanotechnology into RT presents a promising method to increase its efficacy. This review explores various nano-assisted RT strategies aimed at achieving precision treatment. These include using nanomaterials as radiosensitizers, applying nanotechnology to modify the tumor microenvironment, and employing nano-based radioprotectors and radiation-treated cell products for indirect cancer RT. We also explore recent advancements in nano-assisted RT for NSCLC, such as biomimetic targeting that alters mesenchymal stromal cells, magnetic targeting strategies, and nanosensitization with high-atomic number nanomaterials. Finally, we address the existing challenges and future directions of precision RT using nanotechnology, highlighting its potential clinical applications.