An integrated pathogenic framework is described that drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming and highlights novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.
Abstract
Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the tumor suppressor gene FLCN, has traditionally been classified as a classic “mTORopathy” characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation. Synthesizing emerging evidence, we describe an integrated pathogenic framework: biallelic FLCN inactivation drives renal tumorigenesis via constitutive MiT/TFE nuclear accumulation and metabolic reprogramming, whereas haploinsufficiency suffices to disrupt structural integrity in the lung and skin. By reconciling the “mTORC1 paradox” through the lens of gene dosage and temporal signaling dynamics, we highlight novel therapeutic vulnerabilities targeting MiT/TFE factors and kinase rewiring, providing a rationale for organ-specific precision medicine in BHD.
This work provides a comprehensive framework that clarifies recent controversies—such as whether H4K16ac primarily governs transcription or replication timing, and which KAT8-containing complex catalyzes, which acetylation mark—and establishes a rationale for future precision-targeting strategies and biomarker development grounded in KAT8 functional heterogeneity.
This review systematically synthesizes the mechanistic roles of USP2 across various cancers, highlighting its function as a double-edged sword, and comprehensively evaluates the landscape of emerging USP2 inhibitors.
Peng Hao, Jiale Wan, Zhangyu Guo et al.· Biochimica et biophysica act...· 0 citations
A review of the molecular characteristics and physiological functions of USP28, its context-dependent roles in neoplastic diseases, and its translational implications for targeted therapy and biomarker discovery highlights its potential as a therapeutic target for precision medicine.
Tongyong Luo, Shuncai Wu, Qing-Song Wang et al.· Frontiers in Immunology· 1 citation
By critically appraising its substrate diversity and functional versatility, it is proposed that FBXO11 be regarded not merely as a straightforward therapeutic target, but rather as a prognostic biomarker and a context‐specific vulnerability that necessitates precision medicine strategies for effective clinical intervention.
Yuqi Zhang, Changyi Fan, Shiheng Chen et al.· Cancer Science· 0 citations
Threonine tyrosine kinase (TTK) also known as MonoPolar Spindle 1 (Mps1) is a core regulator of the spindle assembly checkpoint (SAC) that ensures accurate chromosome segregation during mitosis. While its canonical role in safeguarding genomic stability is well established, emerging evidence indicates that TTK is frequently overexpressed across a wide range of cancers, where it supports tumor cell survival under conditions of elevated chromosomal instability (CIN). This paradox highlights TTK's dual role as both a guardian of mitotic fidelity and a facilitator of tumor adaptability. Recent studies have demonstrated that pharmacological inhibition of TTK induces mitotic catastrophe by exacerbating chromosome mis-segregation, thereby selectively targeting cancer cells. Several small-molecule TTK inhibitors have entered clinical evaluation, particularly in combination with chemotherapeutic agents and radiotherapy. However, therapeutic responses remain heterogeneous, and the mechanistic basis of tumor-specific reliance on TTK across different cancer contexts remains poorly understood. This review consolidates current knowledge of TTK function beyond its canonical SAC activity, emphasizing its emerging roles in DNA damage response, epithelial-mesenchymal transition, and oncogenic signaling pathways. In addition, the review highlights critical unresolved questions, including the distinction between kinetochore and non-kinetochore functions, and the quantitative thresholds of TTK activity required for checkpoint maintenance. Finally, current advances in TTK-targeted drug development, challenges related to therapeutic selectivity and resistance, along with rational combination therapies and biomarker-guided therapeutic strategies have been summarized. Addressing these challenges will be critical for translating TTK biology into effective therapeutic interventions and for harnessing its potential in precision oncology.
Prachi Patidar, Kritika Jangir, Chainsee Saini et al.· Cell Communication and Signa...· 0 citations
How NUPR1 transduces mitogenic stimuli into anabolic programs, while orchestrating autophagic flux, lysosomal biogenesis, and ferroptosis evasion to maintain cellular fitness under oncogenic and therapeutic stress is examined.
Bo Xiang, Tao Liu, Duo Xu et al.· Frontiers in Physiology· 0 citations
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