Journal of Clinical Investigation最新文献

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment affecting a noteworthy fifty percent of men by age 75, necessitating surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Utilizing a humanized mouse model that replicates elevated skeletal muscle tissue estrogen concentrations akin to aging men, we identified estrogen receptor alpha (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomic analyses on in vitro LAM fibroblasts unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and presenting non-surgical avenues for addressing inguinal hernias.

Fibrosis is the final common pathway leading to end stage chronic kidney disease (CKD). However, the function of protein palmitoylation in renal fibrosis and underlying mechanisms remain unclear. In this study, we observed that the expression of the palmitoyltransferase ZDHHC18 was significantly elevated in unilateral ureteral obstruction (UUO) and folic acid (FA)-induced renal fibrosis mouse models, and was significantly upregulated in the fibrotic kidneys of chronic kidney disease patients. Functionally, tubule-specific deletion of ZDHHC18 attenuated tubular epithelial cells partial epithelial-to-mesenchymal transition (EMT), then reduced production of profibrotic cytokine and alleviates tubulointerstitial fibrosis. In contrast, ZDHHC18 overexpression exacerbated progressive renal fibrosis. Mechanistically, ZDHHC18 catalyzed the palmitoylation of HRAS, which is pivotal for its translocation to the plasma membrane and subsequent activation. HRAS palmitoylation promoted downstream phosphorylation of MEK/ERK and further activated RREB1, enhancing SMAD binding to the Snai1 cis-regulatory regions. Taken together, our findings suggest that ZDHHC18 plays a crucial role in renal fibrogenesis and presents a potential therapeutic target for combating kidney fibrosis.

Constitutively active mutations of KRAS are prevalent in non-small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrated that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits ALKBH5 m6A demethylase activity by regulating post-translational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly DDB2 and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these two genes, thus enhancing NSCLC cells' ability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant-induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5, or by inhibiting METTL3 pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a previously unrecognized mechanism that mediates KRAS mutant-induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTMs-induced m6A modification in DNA damage repair-related genes.

Serotonin (5-HT) is a neurotransmitter that has been linked to tumorigenesis. Whether and how 5-HT modulates cells in the microenvironment to regulate tumor metastasis remains to be largely unknown. Here, we demonstrate that 5-HT is secreted by neuroendocrine prostate cancer (NEPC) cells to communicate with neutrophils and to induce neutrophil extracellular traps (NETs) in the liver, which in turn facilitates the recruitment of disseminated cancer cells and promotes liver metastasis. 5-HT induces histone serotonylation (H3Q5ser) and orchestrates histone citrullination (H3cit) in neutrophils to trigger chromatin decondensation and facilitate the formation of NETs. Interestingly, we uncover in this process a reciprocally reinforcing effect between H3Q5ser and H3cit and a crosstalk between the respective writers TGM2 and PAD4. Genetic ablation or pharmacological targeting of TGM2, or inhibiting 5-HT transporter (SERT) with the FDA-approved antidepressant drug fluoxetine reduces H3Q5ser and H3cit modifications, suppresses NETs formation, and effectively inhibits NEPC, small cell lung cancer, and thyroid medullary cancer liver metastasis. Collectively, the 5-HT-triggered NETs production highlights a new targetable neurotransmitter-immune axis in driving liver metastasis of neuroendocrine cancers.

Sensorineural hearing loss (SNHL) is the most prevalent form of permanent hearing impairment, arising from factors such as aging, exposure to loud noise, disease, ototoxic medications, and genetic mutations. Despite extensive research, effective treatments or cures for SNHL remain elusive. In this issue of the JCI, Lee et al. reveal a link between mutations in ATF6 and SNHL in patients with achromatopsia. The study also shows that Atf6-deficient (Atf6-/-) mice exhibit disorganized stereocilia and age-related loss of outer hair cells. Additionally, the researchers show that Atf6 is critical for cochlear hair cell function. Mice lacking Atf6 expression experienced ER stress, which ultimately led to SNHL. Collectively, these findings enhance our understanding of the emerging role of protein homeostasis and ER stress in the pathogenesis of SNHL.

Colorectal cancer is the second leading cause of cancer death in the United States. The adenomatous polyposis coli (APC) pathway plays a critical role in colorectal tumorigenesis, but the mechanism is not fully understood. In this issue of the JCI, Luo and colleagues used genetically engineered mouse models to show that high mobility group A (HMGA1) is a critical mediator in the development of colon tumors driven by the loss of the Apc gene. HMGA1 activated the transcription of Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2), which regulated intestinal stemness and promoted colon tumorigenesis.

Intestinal stem cells are crucial for maintaining intestinal homeostasis, yet their transformation into tumor stem cells in the context of microbial infection remains poorly understood. Fusobacterium nucleatum is frequently associated with the onset and progression of colorectal cancer (CRC). In this study, we uncovered that F. nucleatum colonized the depths of gut crypts in both patients with CRC and mouse models. Through single-cell sequencing analysis, we demonstrated that F. nucleatum infection reprogrammed crypt cells and activated lymphocyte antigen 6 complex, locus A+ ( LY6A+, also known as stem cell antigen 1 [Sca-1]) revival stem cells (RSCs), promoting their hyperproliferation and subsequent transformation into tumor stem cells, which accelerated intestinal carcinogenesis. Mechanistically, we identified LY6A as a glycosylphosphatidylinositol-anchored (GPI-anchored) membrane receptor for F. nucleatum. Upon binding, F. nucleatum induced the upregulation of ribosomal protein S14 (RPS14) via the LY6A receptor, driving RSC hyperactivity and tumorigenic conversion. Functional studies showed that genetic ablation of Ly6a in intestinal epithelial cells or Rps14 in LY6A+ RSCs substantially reduced F. nucleatum colonization and tumorigenesis. Moreover, analysis of clinical CRC cohorts revealed a strong correlation between F. nucleatum infection, RSC expansion, and elevated RPS14 expression in tumor tissues. These findings highlight an alternative F. nucleatum/LY6A/RPS14 signaling axis as a critical driver of CRC progression and propose potential therapeutic targets for effective CRC intervention.

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain-containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.

Preclinical and clinical observations indicate that the probiotic Lactobacillus rhamnosus GG (LGG) can modulate colonic inflammation. However, the underlying mechanisms have not been explored in depth. Here, we demonstrate that oral administration of live LGG alleviated inflammatory colitis by increasing IL-10 expression in intestinal Ly6C+ monocytes. Mechanistically, LGG induced IL-10 production via the stimulator of IFN genes (STING)/TBK1/NF-κB (RELA) signaling pathway in intestinal Ly6C+ monocytes, enhancing their immune-suppressive function. Elevated IL-10 subsequently activated IL-10 signaling in Ly6C+ monocytes, resulting in an IL-10-based autocrine regulatory loop and inhibition of proinflammatory cytokine production. Furthermore, LGG shifted the gut microbial community and its metabolic functions, leading to intestinal immune responses against colitis. Fecal microbiota transplantation from LGG-colonized mice alleviated immune checkpoint blockade-associated colitis. Our findings highlight the importance of STING signaling in IL-10-dependent antiinflammatory immunity and establish an empirical basis for developing oral administration of live LGG as an efficient and safe therapeutic strategy against inflammatory colitis.

Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy, yet only a fraction of patients respond. Remarkably, gut bacteria impact the efficacy of ICIs in fighting tumors outside of the gut. Certain strains of commensal gut bacteria promote antitumor responses to ICIs in a variety of preclinical mouse tumor models. Patients with cancer who respond to ICIs have a different microbiome compared with that of patients who don't respond. Fecal microbiota transplants (FMTs) from patients into mice phenocopy the patient tumor responses: FMTs from responders promote response to ICIs, whereas FMTs from nonresponders do not promote a response. In patients, FMTs from patients who have had a complete response to ICIs can overcome resistance in patients who progress on treatment. However, the responses to FMTs are variable. Though emerging studies indicate that gut bacteria can promote antitumor immunity in the absence of ICIs, this Review will focus on studies that demonstrate relationships between the gut microbiome and response to ICIs. We will explore studies investigating which bacteria promote response to ICIs in preclinical models, which bacteria are associated with response in patients with cancer receiving ICIs, the mechanisms by which gut bacteria promote antitumor immunity, and how microbiome-based therapies can be translated to the clinic.