Cancer remains the leading cause of mortality worldwide, and the emergence of drug resistance has made the identification of new therapeutic targets imperative. Lactate, traditionally viewed as a byproduct of glycolysis with limited ATP-producing capacity, has recently gained recognition as a critical signaling molecule. It plays a key role not only in cancer cell metabolism but also in shaping the tumor microenvironment (TME). Histone lysine lactylation, a newly identified post-translational modification, has been shown to influence a range of cellular processes in cancer. Current research focuses on the mechanisms and functions of histone lactylation in cancer, including its role in gene expression regulation, signal transduction, and protein synthesis. However, despite these advancements, there are still plenty of barriers in the quest to unravel the mechanisms of lactylation modification. The emergence of single-cell and spatial transcriptomics may offer valuable insights for selecting targets. This review provides a comprehensive summary of the mechanisms and the applications of lactylation modification in clinical settings. Through a detailed analysis, we identify the key challenges and limitations that exist in the current research landscape. These insights lay the groundwork for future studies by highlighting promising research directions.

Parkinson’s disease (PD) is the fastest-growing neurodegeneration disease, characterized typically by a progressive loss of dopaminergic neurons in the substantia nigra, and there are no effective therapeutic agents to cure PD. Rotenone (Rot) is a common and widely used pesticide which can directly inhibit mitochondrial complex I, leading to a loss of dopaminergic neurons. Our previous studies proved that the JWA gene (arl6ip5) may play a prominent role in resisting aging, oxidative stress and inflammation, and JWA knockout in astrocytes increases the susceptibility of mice to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. JWA-activating compound 4 (JAC4) is a small-molecule activator of the JWA gene, but its role in and mechanism against PD have not yet been clarified. In the present study, we showed that the JWA expression level is strongly related to tyrosine hydroxylase (TH) in different growth periods of mice. Additionally, we constructed models with Rot in vivo and in vitro to observe the neuroprotective effects of JAC4. Our results demonstrated that JAC4 prophylactic intervention improved motor dysfunction and dopaminergic neuron loss in mice. Mechanistically, JAC4 reduced oxidative stress damage by reversing mitochondrial complex I damage, reducing nuclear factor kappa-B (NF-κB) translocation and repressing nucleotide-binding domain, leucine-rich-containing family and pyrin domain-containing-3 (NLRP3) inflammasome activation. Overall, our results provide proof that JAC4 could serve as a novel effective agent for PD prevention.

Lung adenocarcinoma (LUAD) is the most common lung cancer, with high mortality. As a tumor-suppressor gene, JWA plays an important role in blocking pan-tumor progression. JAC4, a small molecular-compound agonist, transcriptionally activates JWA expression both in vivo and in vitro. However, the direct target and the anticancer mechanism of JAC4 in LUAD have not been elucidated. Public transcriptome and proteome data sets were used to analyze the relationship between JWA expression and patient survival in LUAD. The anticancer activities of JAC4 were determined through in vitro and in vivo assays. The molecular mechanism of JAC4 was assessed by Western blot, quantitative real-time PCR (qRT-PCR), immunofluorescence (IF), ubiquitination assay, co-immunoprecipitation, and mass spectrometry (MS). Cellular thermal shift and molecule-docking assays were used for confirmation of the interactions between JAC4/CTBP1 and AMPK/NEDD4L. JWA was downregulated in LUAD tissues. Higher expression of JWA was associated with a better prognosis of LUAD. JAC4 inhibited LUAD cell proliferation and migration in both in-vitro and in-vivo models. Mechanistically, JAC4 increased the stability of NEDD4L through AMPK-mediated phosphorylation at Thr367. The WW domain of NEDD4L, an E3 ubiquitin ligase, interacted with EGFR, thus promoting ubiquitination at K716 and the subsequent degradation of EGFR. Importantly, the combination of JAC4 and AZD9191 synergistically inhibited the growth and metastasis of EGFR-mutant lung cancer in both subcutaneous and orthotopic NSCLC xenografts. Furthermore, direct binding of JAC4 to CTBP1 blocked nuclear translocation of CTBP1 and then removed its transcriptional suppression on the JWA gene. The small-molecule JWA agonist JAC4 plays a therapeutic role in EGFR-driven LUAD growth and metastasis through the CTBP1-mediated JWA/AMPK/NEDD4L/EGFR axis.

Tumor heterogeneity limits the precision treatment of targeted drugs. It is important to find new tumor targets. JWA, also known as ADP ribosylation factor-like GTPase 6 interacting protein 5 (ARL6IP5, GenBank: AF070523, 1998), is a microtubule-associated protein and an environmental response gene. Substantial evidence shows that JWA is low expressed in a variety of malignancies and is correlated with overall survival. As a tumor suppressor, JWA inhibits tumor progression by suppressing multiple oncogenes or activating tumor suppressor genes. Low levels of JWA expression in tumors have been reported to be associated with multiple aspects of cancer progression, including angiogenesis, proliferation, apoptosis, metastasis, and chemotherapy resistance. In this review, we will discuss the structure and biological functions of JWA in tumors, examine the potential therapeutic strategies for targeting JWA and explore the directions for future investigation.

Cancer remains a major therapeutic challenge owing to its complex pathogenesis and the limitations of current treatments, such as poor specificity, toxicity, and multidrug resistance. Chromatin accessibility, which is dynamically regulated by genetic, epigenetic, and environmental factors, plays crucial roles in cancer initiation and progression. However, substantial obstacles persist in developing therapeutic strategies that target chromatin accessibility and translating them into clinical practice. This review comprehensively summarizes the biological functions and regulatory mechanisms of chromatin accessibility in tumors, encompassing tumorigenesis, progression, metabolic reprogramming, angiogenesis, stemness, tumor immune microenvironment, and therapy resistance. We integrate comparisons between human and murine models and detail key profiling technologies, including Assay for Transposase‑Accessible Chromatin with high‑throughput sequencing, DNase‑seq, single‑cell multiomics, and three‐dimensional chromatin‑conformation assays. Furthermore, we compile recent preclinical and clinical trials that utilize chromatin accessibility as a biomarker or therapeutic target, along with combination strategies involving chemotherapy, immunotherapy, targeted therapy, and radiotherapy. From a multiomics and interdisciplinary perspective, we discuss current limitations in translating fundamental research into clinical applications and highlight future directions for epigenetics‑based precision oncology.