Gene expression regulated through a set of transcription factors orchestrates the physiologic processes that drive mammary gland development, breast cancer oncogenesis, and breast cancer progression. This review highligh...Gene expression regulated through a set of transcription factors orchestrates the physiologic processes that drive mammary gland development, breast cancer oncogenesis, and breast cancer progression. This review highlights recent progress in our understanding of how transcriptional regulators mediate mammary gland development, mammary oncogenesis and maintenance of breast cancer stem cells, breast cancer phenotype, metastasis, and efforts to target transcription factors as a therapeutic approach in breast cancer.
This research aims to investigate how aberrantly expressed miR-25-3p and EZH2 regulate T cell activation in aplastic anemia (AA) patients and to explore the underlying mechanisms. The study enrolled 26 severe AA (SAA) pa...This research aims to investigate how aberrantly expressed miR-25-3p and EZH2 regulate T cell activation in aplastic anemia (AA) patients and to explore the underlying mechanisms. The study enrolled 26 severe AA (SAA) patients and 22 healthy subjects. Quantitative reverse transcription polymerase chain reaction was used to detect the miR-25-3p, EZH2 and CD69 expression. After establishing an AA mouse model, cell viability, proteins expression levels and cytokines levels were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot analysis, and enzyme-linked immunosorbent assay. A luciferase reporter assay was performed to verify the interaction between miR-25-3p and EZH2. Serum miR-25-3p expression was decreased in SAA patients ( < 0.001). Overexpression of miR-25-3p reduced cell viability and decreased CD69, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) levels; conversely, inhibition of miR-25-3p exerted the opposite effect ( < 0.001). EZH2 was a downstream target gene of miR-25-3p. Overexpression of EZH2 partially reversed the decrease in cell viability and the inhibition of CD69, IFN-γ and TNF-α levels caused by miR-25-3p upregulation ( < 0.01). MiR-25-3p was downregulated in SAA patients and regulated CD4 T cell activation and proliferation by targeting EZH2. These findings provide novel insights into potential therapeutic targets for AA.
A critical developmental process affecting aging and age-associated disease, cell senescence is characterized by persistent growth arrest and adaptive gene expression patterns. A common RNA modification, N6-methyladenosi...A critical developmental process affecting aging and age-associated disease, cell senescence is characterized by persistent growth arrest and adaptive gene expression patterns. A common RNA modification, N6-methyladenosine (mA), regulates gene expression profiles but its impact on senescence has not been studied globally. Here, we elucidated the mA landscape in proliferating and senescent human fibroblasts using epitranscriptomic microarray and mA-crosslinking and immunoprecipitation followed by sequencing (CLIP-Seq) analyses. Our findings revealed that while global mA levels remain stable between proliferating and senescent cells, several transcripts display altered methylation patterns, particularly in senescence-associated pathways like cell cycle, DNA repair, and inflammation. We observed that mA deposition shifted toward 3'-untranslated regions (UTRs) in senescent cells, although the mA site modified (the DRACH motif) was unchanged, and we found a positive correlation between mA levels and transcript abundance. Interestingly, mA was particularly enriched in mRNAs encoding senescence-associated secretory phenotype (SASP) factors, and silencing METTL3, a major mA methyltransferase, reduced the stability of certain SASP mRNAs such as mRNA, suggesting a selective function of mA in fine-tuning the senescent transcriptome. These findings provide insights into the epitranscriptomic regulation of senescence, and highlight mA as a potential intervention target in age-related conditions influenced by senescent cells.
Facilitates chromatin transcription (FACT) is an evolutionarily conserved chromatin remodeling factor. It controls chromatin states in an ATP-independent manner via the regulation of chromatin assembly and disassembly. T...Facilitates chromatin transcription (FACT) is an evolutionarily conserved chromatin remodeling factor. It controls chromatin states in an ATP-independent manner via the regulation of chromatin assembly and disassembly. Through such regulation, FACT is involved in controlling transcription and other DNA-transacting processes such as replication and repair. However, it is surprisingly found to be upregulated in various cancers, and upregulated FACT induces oncogenesis and supports cancer cell survival, aggressiveness and metastasis, thus implying it to be a prognostic marker for cancer with an attractive targeted therapeutic potential. Here, we describe the involvement of FACT in various cancers with mechanistic insights and potential targeted therapeutic implications.
Noncoding RNAs are emerging players in cell signaling and diseases. Recently, we discovered a series of novel lncRNAs that are critical players in inflammation. Here, we demonstrate that hLinfRNA7, a long human noncoding...Noncoding RNAs are emerging players in cell signaling and diseases. Recently, we discovered a series of novel lncRNAs that are critical players in inflammation. Here, we demonstrate that hLinfRNA7, a long human noncoding inflammation-associated RNA 7 (also termed as IDO1-AS6.4) located on the antisense-strand of IDO1 (Indoleamine-2,3 -dioxygenase 1, a tryptophan catabolizing enzyme), plays critical roles in the regulation of inflammation and tryptophan (Trp) catabolism. Our studies demonstrated that hLinfRNA7 expression is induced in human THP1-derived macrophages under inflammation (LPS or IFNγ- stimulation) and is localized in the nucleus. hLinfRNA7 knockdown suppressed LPS-induced IL-6, IL-1β, and iNOS expression and reduced nitric oxide production. Interestingly, hLinfRNA7 knockdown also downregulated the inflammation-induced expression of IDO1 as well as the tryptophan catabolite kynurenine level in macrophages, suggesting critical roles of hLinfRNA7 in inflammation, cytokine regulation, and Trp-catabolism. Furthermore, IDO1 also regulate hLinfRNA7 expression, suggesting their interplay in inflammation and Trp-catabolism. hLinfRNA7 also modulates NF-κB signaling and interacts with an RNA-binding protein, YBX1, which also regulates cytokines, IDO1, hLinfRNA7, and Trp-catabolism under inflammation. Our study demonstrates lncRNA hLinfRNA7 is a novel regulator of inflammation and tryptophan catabolism. By delineating an hLinfRNA7-YBX1-IDO1 axis, our study expands lncRNA roles in immune-metabolic control and inflammatory disease.
Sarcoidosis is a chronic granulomatous disease marked by persistent inflammation and immune cell aggregation, yet its molecular underpinnings remain incompletely understood, hindering the development of effective targete...Sarcoidosis is a chronic granulomatous disease marked by persistent inflammation and immune cell aggregation, yet its molecular underpinnings remain incompletely understood, hindering the development of effective targeted therapies. Here, we report that deletion of Tsc1 or Tsc2 in mice using a Fsp1-Cre leads to spontaneous formation of sarcoid-like granulomas, driven by hyperactivation of the mTORC1 pathway in fibroblasts and interstitial macrophages. Through inflammatory cytokine/chemokine array, we identified CCL24, a chemokine ligand for CCR3, as a key immunoregulatory molecule downregulated in both our murine model and sarcoid cohort plasma. Mechanistically, mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages, uncovering a novel regulatory axis in granuloma formation and maintenance. Pharmacological inhibition using rapamycin and azithromycin markedly attenuated granuloma burden and normalized CCL24-CCR3 signaling, underscoring the therapeutic relevance of this axis. Together, our study establishes a mechanistic link between mTORC1 activation, CCL24-CCR3 dysregulation, and granuloma persistence, offering not only a new insight into molecular mechanisms in sarcoidosis, but also identifying promising targets for clinical intervention.
Small-molecule inhibitors represent a novel potential therapeutic for tumors. Our previous work identified SIC-19, a small molecule compound that induces degradation of salt-inducible kinase 2 (SIK2), leading to apoptosi...Small-molecule inhibitors represent a novel potential therapeutic for tumors. Our previous work identified SIC-19, a small molecule compound that induces degradation of salt-inducible kinase 2 (SIK2), leading to apoptosis and reduced proliferation in tumor, expecting to be a promising clinical treatment for ovarian cancer. While we initially observed that SIC-19 triggers SIK2 ubiquitination, the underlying mechanism was unknown. Here we elucidate this process by demonstrating that SIC-19 promotes the interaction between SIK2 and the CUL4B-DDB1 E3 ubiquitin ligase. Mass spectrometry discovered several ubiquitin ligases that bind to SIK2. Immunoprecipitation assays revealed that the CUL4B-DDB1 ligase is an interaction partner of SIK2. Through Western blot analysis, we demonstrated that CUL4B is functionally required for SIC-19-induced ubiquitination and SIK2 degradation. The ubiquitination and half-life of SIK2 are directly correlated with the dosage of SIC-19 and the expression of CUL4B. Site-directed mutagenesis and ubiquitination assays further confirmed that lysine 144 (K144) is the critical residue in SIK2 that regulates cancer behavior as cell proliferation and migration by leading to the degradation of SIK2. Our findings define a novel mechanism wherein SIC-19 induces CUL4B-dependent ubiquitination and degradation of SIK2, possesses the potential to act as an inhibitor, and may subsequently be developed as a targeted agent.
LaRue-Nolan KC, Flores LF, Vera RE
… +9 more, Sigafoos AN, Hilario Garcia L, Almada LL, Tader BR, Rodriguez-Quevedo MF, May DG, Marks DL, Roux KJ, Fernandez-Zapico ME
Mol Cell Biol
· 2026 May · PMID 42175908
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Full text
Nuclear envelope (NE) proteins are essential for maintaining nuclear morphology, a central process controlling cellular phenotypes. While these proteins and structures are largely characterized in developmental biology,...Nuclear envelope (NE) proteins are essential for maintaining nuclear morphology, a central process controlling cellular phenotypes. While these proteins and structures are largely characterized in developmental biology, their function and associated abnormal nuclear morphology in disease, in particular cancer, remain elusive. We reported that throughout pancreatic transformation, oncogenic mutant KRAS (mKRAS) alters cancer cells nuclear size. Furthermore, we identified the NE protein Emerin as a mediator of these nuclear changes. Emerin's function is versatile and dynamic depending on its protein interactions. Here, using a BioID approach we identified the NE protein, Nesprin-3, as a novel Emerin interactor in mKRAS pancreatic cancer cells. Transcriptomic and epigenomic analyses revealed that mKRAS increases Nesprin-3 expression using the transcription factor KLF5 as an effector. Functional studies demonstrated that Nesprin-3 phenocopies Emerin, where knockdown of Nesprin-3 impaired nuclear morphology, proliferation, and gene expression changes induced by mKRAS. Notably, Nesprin-3 overexpression can rescue the nuclear morphology and proliferative phenotype in pancreatic cancer cells with mKRAS knockdown. Finally, utilizing an Emerin mutant that cannot interact with Nesprin-3 we failed to rescue these nuclear size changes. Our data demonstrate a novel mechanism underlying the oncogenic function of KRAS, a major driver of this dismal condition.
The AP-1-like protein Yap8 is required for arsenic tolerance in the yeast . Previous work has shown that Yap8 binds to arsenic via critical cysteine residues, which converts Yap8 into an active transcriptional regulator...The AP-1-like protein Yap8 is required for arsenic tolerance in the yeast . Previous work has shown that Yap8 binds to arsenic via critical cysteine residues, which converts Yap8 into an active transcriptional regulator of the arsenic detoxification genes and . However, how Yap8 couples arsenic sensing to gene activation is not fully understood. Here, we provide mechanistic insights into Yap8-dependent gene regulation by identifying -regulatory elements and regulatory factors involved. We show that full activation of expression requires two Yap8 binding elements in the promoter, one accessible and one occluded by a nucleosome. Arsenic stress leads to Yap8-dependent chromatin remodeling which enables Yap8 to bind also to the occluded site. We also demonstrate that Yap8 directly interacts with components of the SWI/SNF chromatin remodeling and SAGA histone acetyl transferase complexes and recruits them to the promoter. Accordingly, the -regulatory elements and the SAGA and SWI/SNF complexes are all required for arsenic tolerance. Our data is consistent with a model in which arsenic binding to Yap8 results in gene activation and arsenic tolerance via Yap8-dependent recruitment of coactivators and chromatin remodeling factors to the promoter.
Valosin-containing protein (VCP) is a crucial ATPase involved in maintaining protein homeostasis through the ubiquitin-proteasome system (UPS) and endoplasmic reticulum-associated degradation (ERAD). Dysregulation of VCP...Valosin-containing protein (VCP) is a crucial ATPase involved in maintaining protein homeostasis through the ubiquitin-proteasome system (UPS) and endoplasmic reticulum-associated degradation (ERAD). Dysregulation of VCP has been implicated in neurodegenerative diseases, cancer, and myopathies, and has also been associated with cardiac dysfunction and hypertrophy remodeling. The roles of VCP in the context of cardiomyocyte function and protein homeostasis are still poorly understood. This study examines the effects of pharmacological Vcp inhibition in zebrafish embryos using CB-5083, a selective Vcp ATPase inhibitor. CB-5083-treated embryos exhibited cardiac and skeletal muscle abnormalities, including myofibrillar disorganization, impaired cardiac function, and locomotor defects, closely resembling CRISPR/Cas9-mediated knockout phenotypes. Early developmental inhibition (24-72 hpf) led to severe cardiac impairment and apoptosis, whereas inhibition during late development (72-120 hpf) induced ventricular hypertrophy with preserved contractile function, suggesting a developmental stage-dependent effect. Furthermore, Vcp inhibition was associated with markers of disrupted proteostasis, suggesting UPS dysfunction and ER stress activation. These findings establish a zebrafish model of VCP-related cardiomyopathy, highlight its role in cardiac proteostasis and hypertrophic remodeling, and provide novel insights into disease mechanisms and potential therapeutic targets.
The fascinating world of long non-coding RNAs (lncRNAs) has expanded significantly over the past two decades, and their characterization has revealed their involvement in a variety of biological processes both in physiol...The fascinating world of long non-coding RNAs (lncRNAs) has expanded significantly over the past two decades, and their characterization has revealed their involvement in a variety of biological processes both in physiological and pathological contexts. Here, we review the crosstalk between lncRNAs and the p53 family of transcription factors in cancer, with particular emphasis on the molecular features that enable cells to become malignant, progress, and metastasize. Finally, we discuss how this knowledge is currently being translated into the clinic, including the use of lncRNAs as biomarkers and therapeutic targets.
The stability and activity of CRAF/Raf1 kinase are stringently regulated by heat shock protein 90 (Hsp90). Hsp90-mediated client folding and maturation are governed by its co-chaperones, but their functionality in chaper...The stability and activity of CRAF/Raf1 kinase are stringently regulated by heat shock protein 90 (Hsp90). Hsp90-mediated client folding and maturation are governed by its co-chaperones, but their functionality in chaperoning CRAF kinase to support signaling under physiological conditions remains poorly understood. Here, we show that Hsp70/Hsp90 organizing protein (HOP) associates with CRAF kinase tomaintain its activity and facilitates MAPK pathway activation. This activation is mediated by TPR2A-2B-DP2 domain of HOP and requires efficient binding to Hsp90. Although Cdc37 recruits Hsp90, it cannot compensate for HOP function. Downregulation of HOP/Sti1 in yeast and mammalian cell culture significantly reduces the CRAF signaling. Our data suggest that Hsp90 is recruited to CRAF in two distinct steps: first during folding/maturation via HOP and Cdc37, and later during activation mediated by HOP. Therefore, HOP is a regulator of CRAF kinase during activation of MAPK pathway and serves as a modulator of growth signaling beyond its client folding and maturation function.
Paeonol (Pae) exhibits potent anti-inflammatory and antitumor effects. Chronic atrophic gastritis (CAG) is considered a gastric precancerous lesion, and the JAK2/STAT3 pathway plays a key role in gastrointestinal inflamm...Paeonol (Pae) exhibits potent anti-inflammatory and antitumor effects. Chronic atrophic gastritis (CAG) is considered a gastric precancerous lesion, and the JAK2/STAT3 pathway plays a key role in gastrointestinal inflammation and tumorigenesis. Whether Pae ameliorates CAG by regulating this pathway remains unclear. A 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced malignant transformed cell (MC) model and a CAG rat model were established. The malignant biological behaviors of MC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, clone formation, and Transwell assays. Gastric histopathological changes were examined by pathological staining, inflammatory factors and gastric mucosa-associated factors were detected via enzyme-linked immunosorbent assay (ELISA). Inflammation, proliferation, epithelial-mesenchymal transition (EMT), and the JAK2/STAT3 pathway-related protein expression was analyzed by Western blotting. MC cells exhibited enhanced proliferation, migration, invasion, and EMT, all of which were significantly suppressed by Pae treatment. CAG rats showed severe gastric mucosal damage, intestinal metaplasia, collagen fiber disorganization, and increased Ki-67 expression. Pae treatment alleviated histopathological injury, reduced inflammatory factor levels, and promoted gastric mucosa-associated factor synthesis. Furthermore, Pae markedly inhibited the JAK2/STAT3 pathway in MC cells and gastric tissues. In conclusion, Pae suppresses malignant transformation and alleviates gastric histopathological injury in CAG by modulating the JAK2/STAT3 pathway.
Maintenance of genome integrity is crucial for the survival of an organism. However, our genome is constantly being challenged by several processes that cause cellular stress, resulting in chromosomal instability and the...Maintenance of genome integrity is crucial for the survival of an organism. However, our genome is constantly being challenged by several processes that cause cellular stress, resulting in chromosomal instability and the onset of diseases like cancer. Therefore, cells have evolved many dedicated pathways to preserve genomic integrity. The cell cycle is one of the precisely regulated cellular pathways in which the entire genome is duplicated, and one complete copy of the genome is transferred to each daughter cell. Genome duplication is initiated at the G1 phase, while complete duplication occurs at the S phase. Then, the duplicated genome is equally divided into progeny cells through mitosis. Thus, any deregulation of G1, S, and mitotic phases contributes to genome instability. In this review, we have highlighted the importance of ubiquitin signaling, especially E3 ligases, in maintaining genome integrity during replication and mitosis, as it controls the activation and inactivation of cell cycle regulator proteins.
Acute pancreatitis (AP) is a life-threatening condition driven by premature pancreatic enzyme activation, leading to systemic complications and multi-organ dysfunction. Chaihu Shugan Powder (CSP) has been reported to mit...Acute pancreatitis (AP) is a life-threatening condition driven by premature pancreatic enzyme activation, leading to systemic complications and multi-organ dysfunction. Chaihu Shugan Powder (CSP) has been reported to mitigate pancreatic injury associated with AP, but the detailed regulatory mechanism was unclear. In our study, we investigated the fundamental mechanism of how CSP attenuated AP injury. The AP models were constructed by applying cerulein in AR42J cells and rats. Individual CSP interventions did not affect normal cell function. CSP partially reversed cerulein-induced cell damage, as reflected by increased cell viability, the level of glutathione (GSH), and ferroptosis protein markers but decreased the contents of inflammatory factor, reactive oxygen species (ROS), malondialdehyde (MDA), Fe and iron. CSP activated the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, which in turn reduced ferroptosis in cerulein-exposed AR42J cells. Silencing the PGC-1α gene could partially inhibit the activation of the PGC-1α/Nrf2/HO-1 pathway by CSP in cerulein-induced AR42J cells. In AP rats, CSP alleviated AP-related pathomorphological changes and ferroptosis in rats by activating PGC-1α/Nrf2/HO-1 pathway. Altogether, the mechanism by which CSP alleviated AP injury in rats may be correlated with the activation of PGC-1α/Nrf2/HO-1 pathway.
Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity w...Alternative splicing is a fundamental mechanism that ensures accurate gene expression, supports cellular adaptability, and expands protein diversity beyond the limits of a fixed gene pool. With aging, splicing fidelity weakens, contributing to decline in RNA homeostasis and disrupting essential cellular functions, including mitochondrial oxidative phosphorylation, genome stability, and immune regulation, and in turn accelerating tissue and organ dysfunction. Evidence from senescent cells, aged tissues, and model organisms shows that altered levels of splicing factors and increased RNA polymerase II elongation rates impair co-transcriptional splicing and promote mis-spliced isoforms that reinforce senescence and drive pathology. Dysfunction of RNA-binding proteins further contributes to aberrant splicing, linking splicing defects to age-related diseases such as atherosclerosis, osteoarthritis, sarcopenia, and neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Therapeutic strategies to correct splicing defects, such as antisense oligonucleotides, RNA interference, CRISPR-Cas systems, ADAR-mediated editing, and RNA aptamers, can restore a homeostatic balance of mRNA isoforms. However, major challenges remain, including distinguishing adaptive physiological from pathological splicing 'noise' and achieving targeted delivery to tissues. Despite these obstacles, RNA splicing dysregulation represents a promising avenue to extend health span by reestablishing homeostatic RNA programs, and reinforces the idea that "transcriptomic instability" is a hallmark of aging.
Cancer develops from the unregulated proliferation of cells, influenced by a confluence of genetic mutations and epigenetic modifications that disrupt normal regulatory networks. In recent years, cellular metabolism has...Cancer develops from the unregulated proliferation of cells, influenced by a confluence of genetic mutations and epigenetic modifications that disrupt normal regulatory networks. In recent years, cellular metabolism has emerged as an important factor in controlling epigenetic states by connecting the availability of intracellular metabolites to changes in chromatin. One such metabolite is lactate, a glycolytic by-product produced in large amounts in tumor cells because of the Warburg effect. Lactate has been found to be a substrate for histone lactylation, a recently discovered epigenetic mark that affects gene expression. Although histone lactylation is gaining importance in cancer biology, its functional role in breast cancer remains inadequately elucidated. In this study, we utilized a lactate-deficient cell line created by the knockout of PKM2 to examine the effects of promoter-level histone H3 lysine 18 lactylation (H3K18la) on the regulation of the DNMT3A gene, which subsequently influences SMAD2 expression and modulates the TGF-β signaling pathway and cellular proliferation in breast cancer. Our findings elucidate a novel metabolic-epigenetic axis that cancer cells utilize to drive tumorigenesis.
Gastrointestinal stromal tumor (GIST), the most common gastrointestinal mesenchymal neoplasm, remains poorly understood at the molecular level, limiting precise diagnosis and targeted therapy. This study aimed to systema...Gastrointestinal stromal tumor (GIST), the most common gastrointestinal mesenchymal neoplasm, remains poorly understood at the molecular level, limiting precise diagnosis and targeted therapy. This study aimed to systematically identify key GIST-associated genes through multiomic integration and experimental validation. We analyzed three GIST transcriptomic datasets from GEO, corrected batch effects via surrogate variable analysis (SVA), and identified 61 differentially expressed genes (DEGs) using limma. Weighted gene co-expression network analysis (WGCNA) highlighted progression-related modules, which were refined using random forests and LASSO regression to prioritize C3 and complement factor D (CFD), both of which showed robust diagnostic performance (AUC: 0.928 for C3; 0.955 for CFD). Experimental validation confirmed C3/CFD downregulation in GIST tissues, correlating with advanced stage and poor survival. Functional assays demonstrated their tumor-suppressive roles, inhibiting GIST cell proliferation, colony formation, and migration. CIBERSORT analysis linked C3/CFD to altered immune infiltration, while ssGSEA/GSEA implicated their involvement in lipid metabolism and oxidative phosphorylation. These findings establish C3 and CFD as critical tumor-suppressive biomarkers that modulate the immune response and reprogram metabolism, offering new avenues for GIST diagnosis and therapy.
RNA polymerase I (Pol I) is a specialized eukaryotic enzyme responsible for transcribing ribosomal DNA into precursor rRNA, a process that initiates ribosome biogenesis and supports cellular growth, metabolism, and proli...RNA polymerase I (Pol I) is a specialized eukaryotic enzyme responsible for transcribing ribosomal DNA into precursor rRNA, a process that initiates ribosome biogenesis and supports cellular growth, metabolism, and proliferation. Recent structural and mechanistic studies have revealed unique features of Pol I architecture that enable high transcriptional output and tight regulatory control. Pol I activity is dynamically regulated by signaling pathways, epigenetic mechanisms, and chromatin structure, integrating environmental and metabolic cues to fine-tune ribosome production. Dysregulation of Pol I transcription is associated with a wide spectrum of human diseases: hyperactivation is a hallmark of cancer, whereas loss-of-function mutations cause ribosomopathies, leukodystrophies, and neurodegenerative disorders through nucleolar stress. Targeted therapies, including small-molecule inhibitors and emerging peptide-based approaches, are expanding clinical strategies to modulate Pol I activity. Beyond its canonical role, Pol I contributes to genome stability, immune regulation, and host-pathogen interactions, broadening its therapeutic relevance. This review integrates structural, mechanistic, and disease perspectives on Pol I, highlighting how fundamental discoveries are informing the next generation of targeted interventions across oncology, neurodegeneration, developmental disorders, infection, and aging.