Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet treatment options for advanced disease remain limited. O-GlcNAc transferase (OGT), the enzyme catalyzing O-GlcNAcylation, has been implicated in tumorigenesis, but its pro-cancer mechanism in MASLD-HCC remains poorly defined. Here, we show that OGT expression is significantly upregulated during MASLD-HCC progression and negatively regulates the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) both in vivo and in vitro. Mechanistically, OGT catalyzes O-GlcNAcylation of PTEN at T382, which competitively inhibits the phosphorylation at the same residue. This modification promotes PTEN ubiquitination and accelerates its degradation. Importantly, O-GlcNAcylation of PTEN simultaneously impairs its intrinsic phospholipase activity. These dual effects compromise PTEN function, leading to activation of PI3K/Akt signaling pathway and enhanced tumor cell proliferation and migration. Moreover, pharmacological inhibition of OGT suppresses tumor growth and, when combined with PI3K/Akt pathway inhibitors, produces additive antitumor effects. These findings reveal a novel mechanism by which OGT-mediated O-GlcNAcylation destabilizes and inactivates PTEN, driving MASLD-HCC progression. They also highlight OGT and PTEN as promising therapeutic targets for developing novel strategies against HCC.

Breast cancer brain metastasis (BCBrM) remains a major clinical challenge with limited therapeutic options and poor prognosis. Despite advances in systemic therapy, the incidence of BCBrM is rising due to prolonged survival of patients with advanced breast cancer, yet effective brain-targeted strategies remain scarce, underscoring a critical research gap. This review integrates recent mechanistic insights that illuminate the complex biology underpinning BCBrM and explores how these discoveries are driving therapeutic innovation. We detail the metastatic cascade from local invasion to brain colonization, and examine key signaling pathways orchestrating brain-specific metastasis. Emphasis is placed on the dynamic crosstalk between tumor cells and the brain microenvironment, including astrocytes, microglia, and neurons, as well as metabolic reprogramming and immune evasion. We critically evaluate current preclinical models and their translational relevance, highlighting recent advances in humanized and imaging-based systems. Emerging therapies, such as central nervous system-penetrant kinase inhibitors, antibody–drug conjugates, and immunotherapies, are discussed alongside persistent challenges in drug delivery and resistance. Finally, we outline future directions, calling for cross-disciplinary collaboration and innovative clinical trial designs to personalize care and improve patient outcomes. Together, this review underscores the urgent need to bridge biology and therapy to transform the management of BCBrM.

There is a complex pathological association between neurodegenerative diseases and cancer. The epidemiological negative correlation between Parkinson's disease (PD) and brain tumor is particularly noteworthy. PD is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, while glioma, the representative of brain tumors, originates from the malignant transformation of glial cells. The molecular interaction network between these two diseases is elusive, limiting the development of cross-disease treatment strategies. This review systematically summarizes the associations between PD and glioma in genetic predispositions, epigenetic modifications, alterations in subcellular compartments, and cellular mechanisms concerning neurons, glial cells, and stem cells. Additional links arise from circadian rhythm regulation, oxidative stress, and gut microbiota, underscoring the importance of systemic pathways that connect neurodegeneration and tumorigenesis. Within this context, cancer neuroscience emerges as a critical framework, demonstrating how neuronal activity drives cancer progression by shaping the tumor microenvironment. Therapeutic opportunities build upon these mechanistic insights, including engineering neuron types to suppress cancer growth, modulating synaptic genes, inducing neuronal cell death cascades, and controlling inflammation to disrupt tumor-nerve crosstalk. Emerging neuroscience-inspired technologies may drastically expand the treatment landscape. This review tries to unveil a potential theoretical paradigm for developing precise therapies with both neuroprotection and antitumor effects.