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Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid–liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 ( SNHG9 ) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9 ) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013 ), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM -NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM- NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development. Iron metabolism dysregulation is associated with various diseases including cancer. Here, the authors show that one iron-triggered lncRNA LncRIM regulates cellular iron metabolism effectively by wiring up the Hippo-YAP  signaling pathway and promotes breast cancer development.

Background Endoplasmic reticulum (ER) stress has been implicated in various chronic pain conditions, but its role in trigeminal neuropathic pain (TNP) remains unclear. This study investigates the contribution of ER stress–induced calcium signaling through the inositol trisphosphate receptor 1 (ITPR1) and anoctamin 1 (ANO1) in a mouse model of TNP. Methods A partial infraorbital nerve transection (pIONT) model was used to induce TNP in mice. Mechanical allodynia was assessed using von Frey filaments. ER stress was evaluated via transmission electron microscopy and Western blotting for ER stress markers. Intracellular Ca²⁺ dynamics were measured by Fluo-4 AM-based Ca²⁺ imaging in primary TG neurons. Gene and protein expression were analyzed using qPCR, Western blot, and immunofluorescence. Protein-protein interaction was examined by co-immunoprecipitation. Neuronal excitability and ANO1 currents were recorded by whole-cell patch-clamp. siRNA-mediated knockdown and pharmacological inhibitors were used to interrogate functional contributions. Results pIONT induced pronounced ER stress in TG neurons, evidenced by swollen ER cisternae and upregulated ER stress sensors. Pharmacological alleviation of ER stress in the TG with the chemical chaperone 4-phenylbutyric acid effectively reduced pIONT-induced pain hypersensitivity. Mechanistically, ER stress upregulated the expression of inositol trisphosphate receptor 1 (ITPR1) via the transcription factor RUNX2, and knockdown of RUNX2 attenuated pIONT-induced mechanical allodynia. Moreover, ITPR1 mediates enhanced ER Ca²⁺ release, ERK activation, and the expression of inflammatory mediators, as well as neuronal hyperexcitability in the TG following pIONT. Notably, ITPR1 functionally couples with anoctamin 1 (ANO1), a calcium-activated chloride channel, in TG neurons. An ITPR1 agonist induced ANO1 currents and mechanical allodynia, which were reduced by an ANO1 inhibitor. Finally, knockdown or inhibition of ANO1 reduced neuronal hypersensitivity and TNP pathogenesis. Conclusions ER stress drives TNP through a RUNX2–ITPR1–ANO1 signaling axis: ER stress upregulates RUNX2, which transcriptionally enhances ITPR1 expression, leading to aberrant ER Ca²⁺ release, ERK activation, neuroinflammation, and ANO1-dependent neuronal hyperexcitability. Targeting this pathway may provide a novel therapeutic strategy for TNP.

X-linked inheritance is very rare and is estimated to account for only 1–5% of all nonsyndromic hearing loss cases. We found a multiplex family from China segregating with X-linked nonsyndromic hearing loss. After exclusive analysis of 10 common variations of three hearing loss-related genes, GJB2, mtDNA12srRNA and SLC26A4, a novel truncated variant of SMPX, c.87dupA (p.Gly30Argfs*12) (NCBI ClinVar Submission ID: SUB3136126), was identified by whole-exome sequencing. This variant was co-segregated with hearing loss in the entire family and was absent in 576 unrelated ethnically and geographically matched controls. We also detected a single nucleotide variation in two male controls with normal hearing, SMPX c.55A>G (p.Asn19Asp), which has been annotated as a rare variant in the Single Nucleotide Polymorphism (dbSNP) (rs759552778) and Exome Aggregation Consortium (ExAC) databases. This study has enriched the mutation spectrum of the SMPX gene.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have not been clearly associated with progressive deafness. Herein, we present a deafness locus mapped to chromosome 3p25.1 and an auditory neuropathy spectrum disorder (ANSD) gene, TMEM43, mainly expressed in GLSs. We identify p.(Arg372Ter) of TMEM43 by linkage analysis and exome sequencing in two large Asian families segregating ANSD, which is characterized by inability to discriminate speech despite preserved sensitivity to sound. The knock-in mouse with the p.(Arg372Ter) variant recapitulates a progressive hearing loss with histological abnormalities in GLSs. Mechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced. Based on these mechanistic insights, cochlear implant was performed on three subjects, and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a deafness gene and its causal relationship with ANSD.

Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL.

Genes that are primarily expressed in cochlear glia-like supporting cells (GLSs) have never been clearly associated with progressive deafness. Herein, we present a novel deafness locus mapped to chromosome 3p25.1 and a new auditory neuropathy spectrum disorder (ANSD) gene TMEM43 mainly expressed in GLSs. We identify p.R372X of TMEM43 by linkage analysis and exome sequencing in two large Asian families. The knock-in (KI) mouse with p.R372X mutation recapitulates a progressive hearing loss with histological abnormalities exclusively in GLSs. Mechanistically, TMEM43 interacts with Cx26 and Cx30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.R372X mutation is introduced. Based on the mechanistic insights, cochlear implant was performed on two patients and speech discrimination was successfully restored. Our study highlights a pathological role of cochlear GLSs by identifying a novel deafness gene and its causal relationship with ANSD.