Immune regulation plays a crucial role in human health and disease. Inflammatory bowel disease (IBD) is a chronic relapse bowel disease with an increasing incidence worldwide. Clinical treatments for IBD are limited and inefficient. However, the pathogenesis of immune-mediated IBD remains unclear. This review describes the activation of innate and adaptive immune functions by intestinal immune cells to regulate intestinal immune balance and maintain intestinal mucosal integrity. Changes in susceptible genes, autophagy, energy metabolism, and other factors interact in a complex manner with the immune system, eventually leading to intestinal immune imbalance and the onset of IBD. These events indicate that intestinal immune imbalance is an alarm for IBD development, further opening new possibilities for the unprecedented development of immunotherapy for IBD.

Metastasis of hepatocellular carcinoma (HCC) critically impacts the survival prognosis of patients, with the pivotal role of hepatocellular carcinoma stem cells in initiating invasive metastatic behaviors. The Flap Endonuclease 1 (FEN1) is delineated as a metallonuclease, quintessential for myriad cellular processes including DNA replication, DNA synthesis, DNA damage rectification, Okazaki fragment maturation, baseexcision repair, and the preservation of genomic stability. Furthermore, it has been recognized as an oncogene in a diverse range of malignancies. Our antecedent research has highlighted a pronounced overexpression of protein FEN1 in hepatocellular carcinoma, where it amplifies the invasiveness and metastatic potential of liver cancer cells. However, its precise role in liver cancer stem cells (LCSCs) remains an enigma and requires further investigation. To rigorously evaluate the stemness attributes of LCSCs, we employed sphere formation assays and flow cytometric evaluations. Both CD133+ and CD133- cell populations were discerningly isolated utilizing immunomagnetic bead separation techniques. The expression levels of pertinent genes were assayed via real-time quantitative PCR (RT-qPCR) and western blot analyses, while the expression profiles in hepatocellular carcinoma tissues were gauged using immunohistochemistry. Subsequent immunoprecipitation, in conjunction with mass spectrometry, ascertained the concurrent binding of proteins FEN1 and Small ubiquitin-related modifier 2 (SUMO2) in HCC cells. Lastly, the impact of SUMO2 on proteasomal degradation pathway of FEN1 was validated by supplementing MG132. Our empirical findings substantiate that protein FEN1 is profusely expressed in spheroids and CD133+ cells. In vitro investigations demonstrate that the upregulation of protein FEN1 unequivocally augments the stemness of LCSCs. In a congruent in vivo context, elevation of FEN1 noticeably enhances the tumorigenic potential of LCSCs. Conversely, inhibiting protein FEN1 resulted in a marked reduction in LCSC stemness. From a mechanistic perspective, there exists a salient positive correlation between the protein expression of FEN1 and SUMO2 in liver cancer tissues. Furthermore, the level of SUMO2-mediated modification of FEN1 is pronouncedly elevated in LCSCs. Interestingly, SUMO2 has the ability to bind to FEN1, leading to a inhibition in the proteasomal degradation pathway of FEN1 and an enhancement in its protein expression. However, it is noteworthy that this interaction does not affect the mRNA level of FEN1. In summation, our research elucidates that protein FEN1 is an effector in augmenting the stemness of LCSCs. Consequently, strategic attenuation of protein FEN1 might proffer a pioneering approach for the efficacious elimination of LCSCs.

Hepatocellular carcinoma (HCC) is the prevalent form of primary liver cancer with a high rate of morbidity and death. Ferroptosis is a kind of regulatory cell death mode that depends on iron. Small ubiquitin-like modifier 2 (SUMO2) is linked to HCC progression; however, its role in ferroptosis within HCC remains unclear. Our goal was to evaluate the regulatory effects and molecular mechanisms of SUMO2 in HCC ferroptosis. SUMO2 was screened by bioinformatics analysis, and its expression was verified in HCC tissues. Stable SUMO2 knockdown and overexpression cell lines were created. The downstream target protein acyl-CoA synthetase long-chain family member 3 (ACSL3) of SUMO2 was screened to assessed the mechanism of SUMO2 regulating ferroptosis in HCC cells. In HCC tissues, SUMO2 expression was higher and linked to a worse prognosis for patients. SUMO2 overexpression reduced malondialdehyde content, prevented mitochondrial crest loss, and increased glutathione level under ferroptotic stimuli. Meanwhile, overexpression of SUMO2 lowered the expression of molecules that promote ferroptosis and raised the expression of molecules that prevent it. SUMO2 knockdown produced the opposite effects. Mechanistically, SUMO2 elevated ACSL3 protein level by inhibiting its entry into the ubiquitin–proteasome degradation pathway and enhanced its protein stability. The inhibitory effects of SUMO2 on ferroptosis in HCC cells were reversed by ACSL3 knockdown in SUMO2-overexpressing cells. In summary, SUMO2 binds to ACSL3, preventing its protein degradation, thereby increasing its protein stability and level, which in turn negatively regulates ferroptosis in HCC cells. These results point to interesting targets and therapeutic approaches for HCC.

HCC remains a leading cause of cancer‐related mortality, and effective therapies are limited. SMC1A, a core subunit of the cohesin complex involved in chromatin organization and transcriptional control, has not been fully characterized in HCC. SMC1A expression and prognostic value were analyzed using ICGC and single‐cell datasets, and validated in tissue microarrays and clinical specimens. Functional roles were examined in vitro, in vivo, and in patient‐derived organoids. Mechanistic studies combined transcriptomic, chromatin, and post‐transcriptional analyses to define downstream transcriptional regulation and upstream m6A‐dependent control. Therapeutic delivery was assessed using siRNA‐loaded LNPs. SMC1A was significantly upregulated in HCC and associated with poor prognosis. SMC1A knockdown suppressed proliferation, migration, invasion, and organoid growth, reduced tumor burden in xenograft and primary models, and promoted apoptosis. Nestin was identified as a transcriptional target of SMC1A; SMC1A facilitated enhancer–promoter interactions to activate Nestin transcription, and Nestin overexpression rescued malignant phenotypes after SMC1A depletion. Upstream, IGF2BP1 bound m6A‐modified regions within the SMC1A 3′‐UTR, stabilized SMC1A mRNA, and maintained the SMC1A–Nestin axis. Systemic LNP‐siSMC1A accumulated in the liver and inhibited tumor growth. SMC1A drives HCC progression through Nestin‐associated chromatin regulation and is maintained by IGF2BP1‐mediated m6A stabilization. LNP‐based silencing of SMC1A suppresses HCC.

Background: This study aimed to identify potential therapeutic targets for sepsis and elucidate the underlying molecular mechanisms, with a particular focus on the liver as a key target organ for experimental validation. Methods: Here, two sequential studies were conducted to uncover and characterize therapeutic targets involved in sepsis-induced liver injury. In Study 1, a proteome-wide Mendelian randomization (MR) analysis was performed using protein quantitative trait loci from deCODE ( n = 35 559 Icelanders), UK Biobank ( n = 54 219), ARIC ( n = 7213 European Americans; n = 1871 African Americans), AGES-Reykjavik ( n = 5368 Icelanders), and Fenland ( n = 10 708 European ancestry). These datasets were integrated with a sepsis genome-wide association study (GWAS) (FinnGen R12; n = 17 133 cases and 439 048 controls) to identify causal protein candidates. Subsequently, summary-data-based MR was performed. The analysis was based on data from eQTLGen ( n = 31 684), GTEx v8 ( n = 838 donors), and sepsis GWAS (FinnGen R12; UK Biobank, n = 11 643 cases/474 841 controls). Its goal was to prioritize genes concordant with protein signals. Expression of the candidate was then validated in vivo and in vitro . In Study 2, a metabolite GWAS ( n = 8299) was used to investigate metabolic mediation and perform pathway enrichment analysis. Finally, potential small-molecule therapeutics predicted to modulate the prioritized target were identified. Results: Integrated multi-omics analyses identified tubulin-folding cofactor B (TBCB) as a promising therapeutic target for sepsis. Quantitative analyses in both in vivo and in vitro models consistently demonstrated significant upregulation of TBCB during sepsis-induced liver injury. Functional knockdown of TBCB significantly attenuated inflammatory signaling. Mechanistically, TBCB appears to contribute to sepsis progression by modulating intracellular lipid metabolism and metabolic homeostasis. Furthermore, molecular docking and dynamics simulations predicted several small molecules for TBCB, suggesting potential therapeutic value. Conclusion: This study identifies TBCB as a central regulator of sepsis pathogenesis, especially in sepsis-induced liver injury. These findings provide novel mechanistic insights and a promising therapeutic target for intervention.