p62/SQSTM1 is a multifunctional adaptor protein playing a central role in the regulation of autophagy and stress response pathways in higher eukaryotes. However, its functional relevance in lower eukaryotes like remains...p62/SQSTM1 is a multifunctional adaptor protein playing a central role in the regulation of autophagy and stress response pathways in higher eukaryotes. However, its functional relevance in lower eukaryotes like remains largely unexplored. In this study, we demonstrate that p62 is crucial for cAMP-mediated development and autophagy. Loss of p62 alters levels of intracellular glucose, cAMP, ubiquitinated proteins and autophagic flux. These defects result in impaired cell aggregation and abnormal fruiting body formation, accompanied by reduced spore viability. Interestingly, pulsing of null cells with exogenous cAMP could partially rescue the developmental defects, implicating a role of p62 in maintaining the intracellular cAMP levels required for starvation stress-induced development. p62 also influences cell-fate decisions during development as its deletion biases cells toward pre-spore differentiation, whereas overexpression promotes pre-stalk lineage. Mechanistically, p62 also modulates autophagy flux potentially via regulating AMPK levels along with cAMP dynamics. Together, these findings position p62 as an evolutionarily conserved key adaptor protein that provides new insights into the molecular mechanisms underlying multicellular development.
Telomeres are crucial for maintaining chromosomal integrity and are characterized by repetitive DNA sequences, which may be stabilized by the shelterin protein complex or by formation of secondary structures, such as G-q...Telomeres are crucial for maintaining chromosomal integrity and are characterized by repetitive DNA sequences, which may be stabilized by the shelterin protein complex or by formation of secondary structures, such as G-quadruplexes (G4 DNA). Frequently, subtelomeric regions are decorated with di- and tri-methylated lysine 27 on histone H3 (H3K27me), repressive marks catalyzed by Polycomb Repressive Complex 2 that are associated with facultative heterochromatin in many eukaryotes. Our previous work with the filamentous fungus demonstrated that native telomere repeats induce H3K27me at ectopic loci. Here we report investigations into the mechanism of this and demonstrate that some non-native telomere repeats can also induce H3K27me. Hi-C analyses demonstrated that ectopic telomeric repeats can interact with native telomeres. Chromatin immunoprecipitation (ChIP) experiments with an anti-G4-DNA antibody showed that establishment of H3K27me was not correlated with the presence of G4 DNA. Other ChIP experiments demonstrated that the telomere repeat-binding protein TRF-1, which has been demonstrated to be a member of the shelterin complex in other systems, binds to interstitial telomere repeats that induce H3K27me. Tethering experiments revealed that TRF-1 binding is sufficient to induce H3K27me. Together these results suggest that TRF-1 plays a crucial role in establishment of H3K27me, and thus repression, at telomere sequences.
Copper is an essential but potentially toxic nutrient required for a variety of biological functions. Mammalian cells use a complex network of copper transporters and metallochaperones to maintain copper homeostasis. Pre...Copper is an essential but potentially toxic nutrient required for a variety of biological functions. Mammalian cells use a complex network of copper transporters and metallochaperones to maintain copper homeostasis. Previous work investigating the role of copper in various disease states has highlighted the importance of copper transporters and metallochaperones. However, questions remain about how copper distribution changes under dynamic conditions like tissue differentiation. We previously reported that the copper exporter ATP7A is required for skeletal myoblast differentiation and that its expression changes in a differentiation dependent manner. Here, we sought to further understand the ATP7A-mediated copper export pathway by examining ATOX1, the copper chaperone that delivers copper to ATP7A. To investigate the role of ATOX1 in a dynamic cellular context, we characterized its protein-protein interactions during myoblast differentiation using the proximity labeling protein APEX2 to biotinylate proteins near ATOX1. We discovered that the ATOX1 interactome undergoes dramatic changes as myoblasts differentiate. These dynamic interactions correlate with distinct phenotypes of ATOX1 deficiency in proliferating and differentiated cells. Together, our results highlight the dynamic interactome of ATOX1 and its contribution to myoblast differentiation.
Transcription factors (TFs) are traditionally classified as activators or repressors, yet some can perform both roles. We highlight well-supported examples of dual activator/repressor functions and review the mechanisms...Transcription factors (TFs) are traditionally classified as activators or repressors, yet some can perform both roles. We highlight well-supported examples of dual activator/repressor functions and review the mechanisms that explain how duality arises. These examples reveal that transcriptional duality arises from three recurring mechanisms: positional effects, cofactor exchange, and regulatory switches. Even within these recurring mechanisms, the precise molecular details diverge, with regulatory outcomes dictated by differences in TF positioning, cofactor availability, modification state, and ligand binding. We propose that future work should move beyond descriptive labels of and instead focus on elucidating the precise molecular mechanisms by which TFs function to elicit opposing regulatory effects.
Transposable elements (TEs) are indispensable components of eukaryotic genomes, mechanistically linked to carcinogenesis, aging and other degenerative diseases. The ability of TEs to self-propagate and cause deletions, i...Transposable elements (TEs) are indispensable components of eukaryotic genomes, mechanistically linked to carcinogenesis, aging and other degenerative diseases. The ability of TEs to self-propagate and cause deletions, inversions or insertions within the genome poses a real threat to the fidelity of genomic integrity. This review discusses the fundamental properties of TEs, with a focus on cellular interactions associated with mechanisms involved in recombination, replication, and DNA repair. Since mobilization of TEs induces double-strand breaks (DSBs), faulty repair mechanisms could lead to cellular dysfunction, pathology and death. The TE-induced DNA DSB repair cascade follows either homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways. Importantly, epigenetic regulatory mechanisms including DNA methylation and histone acetylation provide additional control in ensuring accurate DNA repair and could prove to be key targets for therapeutic intervention.
Cellular senescence has a dual role in both tumor suppression and the promotion of age-related diseases. This paradox suggests the existence of functionally distinct "beneficial" and "detrimental" senescent states, yet t...Cellular senescence has a dual role in both tumor suppression and the promotion of age-related diseases. This paradox suggests the existence of functionally distinct "beneficial" and "detrimental" senescent states, yet the molecular basis that governs their fate has remained elusive. Here, we reveal that the dynamic exchange of histone H2AX on chromatin functions as an essential quality control mechanism that dictates the quality of senescence. We demonstrate that the histone acetyltransferase TIP60, in complex with the chaperone FACT, acetylates H2AX at lysine 5 (K5), which in turn drives its dynamic exchange. This histone exchange is indispensable for promoting the degradation of the DNA damage response mediator MDC1, a process we uncover is mediated by a novel DNA-PKcs-p97 signaling axis. Disruption of this TIP60-FACT-H2AX exchange pathway leads to the hyperaccumulation of MDC1 and a shift toward error-prone nonhomologous end joining (NHEJ), inducing a pathological senescent state with oncogenic potential. Our study redefines histone exchange from a passive chromatin event to an active regulatory hub that determines the fate of aging cells. These findings provide a molecular basis for the heterogeneity of senescence and establish a rationale for developing "senomorphic" therapies aimed at improving the quality of aging.
A-to-I RNA editing introduces A-to-G variation at post-transcriptional level, but it remains mysterious. What is the advantage of functional RNA editing compared to an A/G heterozygous SNP? Here, we provide the following...A-to-I RNA editing introduces A-to-G variation at post-transcriptional level, but it remains mysterious. What is the advantage of functional RNA editing compared to an A/G heterozygous SNP? Here, we provide the following situations that particular RNA editing sites can be superior to heterozygous SNPs even independent of its temporospatial regulation. (1) Assume a site with A/G heterozygote advantage. RNA editing does not undergo Mendelian segregation and recombination that inevitably produce homozygotes of lower fitness. (2) Graded RNA editing level. A snapshot of editing profile shows strong tissue-specific editing levels, providing flexible stoichiometry of edited/unedited versions, while heterozygous SNPs generally produce similar expression of two alleles. (3) Higher molecular diversity. N RNA editing sites in a gene theoretically produce a dramatic number of X = 2 mRNA haplotypes, but all SNPs in a gene can only produce two alleles. Nevertheless, we emphasize that these advantageous sites may emerge through complicated evolutionary process and remain rare across the genome. We systematically discussed the pros and cons of RNA editing versus heterozygous SNPs, deepening our understanding of the biological functions of -regulatory mechanisms. We provide putative answers to why evolution chose RNA editing instead of a genomic mutation at particular sites.
The brain is one of the most lipid-rich organs, reflecting the critical role of lipid metabolism in neuronal and glial cell function. While mitochondria are central to energy metabolism, calcium signaling, and cell death...The brain is one of the most lipid-rich organs, reflecting the critical role of lipid metabolism in neuronal and glial cell function. While mitochondria are central to energy metabolism, calcium signaling, and cell death, they do not utilize lipid oxidation for energy but rely on lipids for membrane integrity and intracellular communication. Here we review the interactions between lipids and mitochondria in intracellular signaling within brain cells, examining their roles in normal physiology and the mechanisms underlying major neurodegenerative diseases. Alterations in lipid homeostasis and mitochondrial metabolism are implicated in neurodegeneration, highlighting the importance of lipid-mediated mitochondrial signaling pathways. Understanding these interactions provides insights into cellular dysfunction in neurodegenerative disorders and may inform future therapeutic strategies targeting lipid and mitochondrial pathways.
This study elucidates the molecular mechanism by which Xiangpi Shengji ointment (Xiangpi Shengji gao, XPSJG) promotes anal fistula wound healing. Integrated network pharmacology and transcriptomic analyses (GSE28914, GSE...This study elucidates the molecular mechanism by which Xiangpi Shengji ointment (Xiangpi Shengji gao, XPSJG) promotes anal fistula wound healing. Integrated network pharmacology and transcriptomic analyses (GSE28914, GSE203244) revealed the involvement of the NF-κB/HIF-α/VEGF axis, with elevated expression of NF-κB, HIF1A, and VEGFA observed during the early healing phase (days 3 and 7). Single-cell RNA sequencing further indicated that activation of this signaling axis may drive early macrophage M1 polarization. In vitro experiments confirmed early treatment with the aqueous extract of XPSJG powder significantly enhanced macrophage M1 polarization and upregulated VEGF, COL1A1, and α-SMA, promoting fibroblast proliferation and migration (assessed via CCK-8, ELISA, WB, RT-qPCR). In vivo, using a murine anal fistula model, XPSJG accelerated wound closure, improved tissue architecture, and reduced inflammation and apoptosis through modulation of the NF-κB/HIF-α/VEGF axis. These effects were partially reversed by an NF-κB inhibitor, further verifying pathway involvement. Collectively, the findings demonstrate that early application of XPSJG facilitates anal fistula healing by inducing macrophage M1 polarization and enhancing fibroblast function via the NF-κB/HIF-α/VEGF signaling axis, thereby providing a mechanistic rationale for its clinical use in chronic wound management.
Regulation of gene expression at the messenger RNA (mRNA) level is crucial for organisms to rapidly respond to changing environmental conditions, especially harmful toxins. The highly conserved nonsense-mediated mRNA dec...Regulation of gene expression at the messenger RNA (mRNA) level is crucial for organisms to rapidly respond to changing environmental conditions, especially harmful toxins. The highly conserved nonsense-mediated mRNA decay (NMD) pathway is a translation dependent messenger RNA (mRNA) degradation pathway. Although NMD is well known for targeting mRNAs with premature termination codons (PTCs), it is now recognized as a pathway with additional essential regulatory functions. Notably, NMD precisely regulates protein coding natural mRNAs, hence controlling gene expression within several physiologically significant pathways. Pathways controlled by NMD include essential bio-metal homeostasis and metal ion detoxification, and the crosstalk between them. Here, we discuss the relationships between NMD and various metal ion detoxification pathways. We review the role that the NMD pathway plays in cadmium, arsenic, and lithium detoxification.
Rho GTPases are Ras-like proteins that contribute to many aspects of human cancer. However, unlike Ras, Rho proteins are not often mutagenically activated in cancers, but require activation by upstream proteins known as...Rho GTPases are Ras-like proteins that contribute to many aspects of human cancer. However, unlike Ras, Rho proteins are not often mutagenically activated in cancers, but require activation by upstream proteins known as Rho GDP exchange factors (RhoGEFs). The neuroepithelial transforming gene 1 (Net1) is a RhoA/RhoB-specific GEF that is overexpressed in many cancers, and high levels of Net1 protein expression often correlate with reduced disease-free and overall survival. Net1 promotes multiple phenotypes in cancer cells, including cell motility, invasion, and proliferation. It does so by regulating diverse signaling pathways that ultimately control actin cytoskeletal organization, transcription, DNA damage signaling, and mitosis. In tumors, Net1 is required for tumor cell proliferation, tumor angiogenesis, and distant metastasis. In this review we will delineate the evidence supporting a role for Net1 in tumor progression, and describe mechanisms that regulate Net1 expression and cellular activity.
During genotoxic stress, mammalian cells adapt to resume transcription after repair of damaged DNA. However, mechanisms of these adaptations leading to optimal transcriptional restart are poorly known. In this study, we...During genotoxic stress, mammalian cells adapt to resume transcription after repair of damaged DNA. However, mechanisms of these adaptations leading to optimal transcriptional restart are poorly known. In this study, we show critical role of EAF1-mediated enhanced phase separation of elongation factor ELL in its interaction with DNA repair factors for efficient repair of damaged DNA and subsequent transcriptional restart. ELL protein has intrinsic ability to phase separate and form liquid condensates both in vitro and in vivo within mammalian cells. Upon association with EAF1, intrinsic phase separation ability of ELL is enhanced resulting in changes in material property of ELL●EAF1 condensates. Physiologically, upon exposure to genotoxic stress, ATM-mediated phosphorylation-dependent increased EAF1 binding leads to enhanced phase separation and changes the material property of ELL. This, in turn, causes its increased interaction with DNA-PKc and associated Ku complex components. This increased interaction is important for their optimal recruitment on chromatin and corresponding repair of damaged DNA and transcriptional restart. An EAF1 knockdown or ELL mutant that fails to show its enhanced interaction with EAF1 during DNA damage, also fails to show efficient DNA damage repair, transcriptional restart and cell survival after exposure to genotoxic stress.
To maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors maintain telomeres using telomerase, a subset of tumors utilize a DNA-templated process termed alternative...To maintain genome stability, proliferating cells must enact a program of telomere maintenance. While most tumors maintain telomeres using telomerase, a subset of tumors utilize a DNA-templated process termed alternative lengthening of telomeres or ALT. ALT is associated with mutations in the ATRX/DAXX/H3.3 histone chaperone complex, which is responsible for deposition of histone variant H3.3 at heterochromatic regions of the genome including telomeres. We wished to better understand the role DAXX plays in ALT suppression, and to determine which disease-associated DAXX mutations are unable to suppress ALT. To answer this question, we leveraged the G292 cell line, in which ATRX is wild-type but DAXX has undergone a fusion event. Restoration of wild-type DAXX in G292 localizes ATRX and abrogates ALT. Using this model system, we tested the ability of disease-associated DAXX missense variants to suppress ALT. Missense mutations in the ATRX binding domain, the histone binding domain, and the C-terminal SUMO interaction motif reduce the ability of DAXX to suppress ALT. Unexpectedly, we find that mutations in the DAXX histone binding domain lead to failure of ATRX localization. We conclude that a key function of DAXX in ALT suppression is the localization of ATRX to nuclear foci.
The PAQosome (R2TP/PFDL complex) is a recently characterized co-chaperone of Hsp90 that orchestrates the assembly and stabilization of diverse macromolecular protein complexes essential for cellular homeostasis. It consi...The PAQosome (R2TP/PFDL complex) is a recently characterized co-chaperone of Hsp90 that orchestrates the assembly and stabilization of diverse macromolecular protein complexes essential for cellular homeostasis. It consists of RUVBL1, RUVBL2, PIH1D1, RPAP3 and a PFDL module consisting of prefoldin and prefoldin-like proteins. RPAP3 and PIH1D1 are subunits exclusively for the R2TP complex, and they act as central adaptors through their interactions with RUVBL1/2, Hsp90 and clients. Originally described in the context of ribonucleoprotein and PIKK assembly, evolving evidence now implicates PIH1D1 and RPAP3 in a broad spectrum of biological processes, including ciliogenesis, RNA silencing, DNA damage response, metabolic regulation, and oncogenesis. The mechanistic basis of substrate recognition, the phosphorylation-independent interactions, and the functional contribution of alternative PAQosome assemblies remain limited. This review highlights PIH1D1 and RPAP3 as dynamic proteins at the crossroads of protein homeostasis, signaling pathways, and diseases.
Shc family adaptor proteins are involved in diverse signaling pathways that regulate critical cellular functions, including proliferation, differentiation, migration, and survival. ShcD is the most recently isolated memb...Shc family adaptor proteins are involved in diverse signaling pathways that regulate critical cellular functions, including proliferation, differentiation, migration, and survival. ShcD is the most recently isolated member and while previous studies have identified its prominent expression in the brain, specifically within the olfactory bulb, its physiological functions remain largely unknown. Here we report initial characterization of ShcD knockout (ShcD) mice and identify structural, behavioral, and biochemical deficits associated with ShcD deletion. Specifically, ShcD mice have decreased olfactory bulb weight with a corresponding reduced granule cell layer compared to controls, and defects in olfactory performance. Intriguingly, ShcD mice display increased proliferation in the subventricular zone, which serves as the reservoir for neural progenitors migrating into the olfactory bulb. Supporting these cellular changes, we noted Erk2 hyperactivation in the olfactory bulb of ShcD mice, and using a cultured neuron model, we also detected altered signaling of Erk5, a MAPK protein associated with neural stem cell differentiation, as well as increased p66ShcA expression, indicating a potential compensatory mechanism within the Shc family. These results uncover a possible physiological role for ShcD in neurogenesis and imply its involvement in signaling pathways that regulate stem cell maintenance and/or differentiation.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogene...Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal cell death, brain atrophy, and cognitive decline. Aggregation of Tau protein in neurons is a critical factor in the pathogenesis of AD. Tau aggregates increase as the disease progresses and contribute to neuronal cell death. This study investigated the role of ubiquitin-specific protease 10 (USP10) in Tau pathology and neuronal viability in AD. We found that the expression of USP10 was reduced in the brains of late-stage AD patients with severe Tau aggregate accumulation, which correlated with increased neuronal apoptosis. Mechanistically, our results suggest that USP10 downregulation in late-stage AD may be due to its degradation by the accumulation of p62, an inducer of selective autophagy. Brain-specific knockout mice show increased neuronal apoptosis during embryonic development and postnatal brain atrophy. In the P301S-Tau transgenic mice, heterozygous knockout lowered Tau levels and slightly improved early survival, suggesting USP10 has stage-dependent effects: its reduction lessens Tau burden early but worsens neuronal loss in late stage. This study identifies USP10 as a key regulator of Tau pathology and neuronal survival in AD.
Inflammation and ferroptosis play a crucial role in cisplatin (CP)-induced acute kidney injury (AKI). Silybin (SYB), a polyphenolic flavonoid, has shown renal protective effects, but its underlying mechanisms remain uncl...Inflammation and ferroptosis play a crucial role in cisplatin (CP)-induced acute kidney injury (AKI). Silybin (SYB), a polyphenolic flavonoid, has shown renal protective effects, but its underlying mechanisms remain unclear. CP-induced HK-2 cell and mouse AKI models were used to explore the role of SYB. CCK-8, lactate dehydrogenase release, flow cytometry, and calcein/PI staining, were performed to evaluate cell viability, proliferation, and apoptosis. Oxidative stress and ferroptosis markers were measured, while renal function was assessed by serum creatinine and urea nitrogen. Mitochondrial ultrastructure was examined, and histological staining was conducted to analyze renal pathology and iron deposition. Western blotting detected HDAC6, NF-κB, NLRP3, and ferroptosis-related proteins expression. SYB treatment alleviated CP-induced mitochondrial damage, reduced lactate dehydrogenase release, inflammatory cytokines, oxidative stress, and ferroptosis, and improved proliferation and viability in HK-2 cells. In mice, 100 mg/kg SYB decreased serum creatinine, urea nitrogen, and cytokine levels, while ameliorating renal tissue injury. Mechanistically, SYB downregulated HDAC6 and inhibited NF-κB/NLRP3 activation, thereby suppressing ferroptosis. Notably, overexpression of HDAC6 restored NF-κB/NLRP3 activity and attenuated the protective effects of SYB. In conclusion, SYB mitigates CP-induced AKI by reducing inflammation and ferroptosis by modulating the HDAC6/NF-κB/NLRP3 pathway.
The serine/threonine kinase, TOR (target of rapamycin), exists in two complexes, namely TORC1 (with either Tor1 or Tor2 kinase) and TORC2 (that contains Tor2, but not Tor1), and its pharmacological inhibition by rapamyci...The serine/threonine kinase, TOR (target of rapamycin), exists in two complexes, namely TORC1 (with either Tor1 or Tor2 kinase) and TORC2 (that contains Tor2, but not Tor1), and its pharmacological inhibition by rapamycin impairs the PIC (pre-initiation complex) formation at the ribosomal protein genes (and hence transcription and ribosome biogenesis). However, TOR's involvement in such gene regulation has not been elucidated genetically at the level of Tor1, Tor2, TORC1 or TORC2. Here, we demonstrate that null mutation of and short-term depletion of its expression do not affect the PIC formation (and transcription) at the ribosomal protein genes. Likewise, PIC formation and transcription are not altered in TORC2-specific -tsA conditional mutant or following short-term depletion of expression. These results support the dispensability of TORC2 for ribosomal protein gene expression, and indicate that Tor1 and Tor2 play redundant roles via TORC1 for PIC formation, and hence transcription. In agreement, the mutant in combination with both TORC1 and TORC2-specific tsC conditional mutation impairs PIC formation at the ribosomal protein genes with consequent reduction in transcription. Collectively, our genetic analysis support redundant, yet distinct, functions of Tor1 and Tor2 via TORC1, not TORC2, in regulation of the ribosomal protein gene expression.
McMurdie K, Peeney AN, Mefford MA
… +2 more, Baumann P, Zappulla DC
Mol Cell Biol
· 2026 Jan · PMID 41296594
·
Full text
The telomerase RNA-protein enzyme is critical for most eukaryotes to complete genome copying by extending chromosome ends, thus solving the end-replication problem and postponing senescence. Despite the importance of the...The telomerase RNA-protein enzyme is critical for most eukaryotes to complete genome copying by extending chromosome ends, thus solving the end-replication problem and postponing senescence. Despite the importance of the fission yeast to biomedical research, very little is known about the structure of its 1212 nt telomerase RNA. We have determined the secondary structure of this large RNA, TER1, based on phylogenetics and bioinformatic modeling, as well as genetic and biochemical analyses. We find several conserved regions of the rapidly evolving TER1 RNA are important to maintain telomeres, based on testing truncation mutants , whereas many other large regions are dispensable. This is similar to budding yeast telomerase RNA, and consistent with functioning as a flexible scaffold for the RNP. We tested if the essential three-way junction works from other locations in TER1, finding that it can, supporting that it is flexibly scaffolded. Furthermore, we find that a half-sized Mini-TER1 allele, built from the catalytic core and the three-way junction, reconstitutes catalytic activity with TERT . Overall, we provide a secondary structure model for the large fission-yeast telomerase lncRNA, based on phylogenetics and molecular-genetic testing in cells, and insight into the RNP's physical and functional organization.
Ulcerative colitis (UC) is a clinically common idiopathic inflammatory bowel disease. The DSS-induced colitis model was induced via 5% DSS for 7 days. Rats were gavaged with QLJCN solution in different concentrations. Th...Ulcerative colitis (UC) is a clinically common idiopathic inflammatory bowel disease. The DSS-induced colitis model was induced via 5% DSS for 7 days. Rats were gavaged with QLJCN solution in different concentrations. This study measured body weight, colon length, and DAI of rats in each group. The hematoxylin-eosin staining assessed the histopathology and histological score. Western blot analysis examined the expressions of TFF3, MUC-2, JAK2/STAT3 pathway-, and TLR4/NF-κB pathway-related markers. Moreover, the contents of IL-6, TNF-α, and LPS in the colons/serum were determined by ELISA. TLR4 activator (RS09) or JAK2/STAT3 activator (colivelin) were employed for the rescue experiments. QLJCN repressed weight loss and the increase of DAI score in DSS rats. QLJCN also increased the colon length and alleviated colonic damage, and effectively repressed the levels of IL-6 and TNF-α but elevated the levels of TFF3 and MUC-2 in the colons/serum of DSS rats. Moreover, QLJCN weakened the activation of JAK2/STAT3 and TLR4/NF-κB pathways, and alleviated the intestinal inflammation. Furthermore, these ameliorative effects of QLJCN were reversed by TLR4 activator (RS09) or JAK2/STAT3 activator (colivelin). QLJCN has protective effects on DSS-induced colitis rats by restraining JAK2/STAT3 and TLR4/NF-κB pathways. This study provides new therapeutic strategies for UC.