Tuberculosis caused by Mycobacterium tuberculosis (Mtb) infection remains a large global public health problem. One striking characteristic of Mtb is its ability to adapt to hypoxia and trigger the...

Kirsten rat sarcoma virus (KRAS) mutation is associated with malignant tumor transformation and drug resistance. However, the development of clinically effective targeted therapies for KRAS-mutant cancer has proven to be a formidable challenge. Here, we report that tripartite motif-containing protein 21 (TRIM21) functions as a target of extracellular signal-regulated kinase 2 (ERK2) in KRAS-mutant colorectal cancer (CRC), contributing to regorafenib therapy resistance. Mechanistically, TRIM21 directly interacts with and ubiquitinates v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) at lysine 148 (K148) via K63-linkage, enabling c-Myc to be targeted to the autophagy machinery for degradation, ultimately resulting in the downregulation of enolase 2 expression and inhibition of glycolysis. However, mutant KRAS (KRAS/MT)-driven mitogen-activated protein kinase (MAPK) signaling leads to the phosphorylation of TRIM21 (p-TRIM21) at Threonine 396 (T396) by ERK2, disrupting the interaction between TRIM21 and c-Myc and thereby preventing c-Myc from targeting autophagy for degradation. This enhances glycolysis and contributes to regorafenib resistance. Clinically, high p-TRIM21 (T396) is associated with an unfavorable prognosis. Targeting TRIM21 to disrupt KRAS/MT-driven phosphorylation using the antidepressant vilazodone shows potential for enhancing the efficacy of regorafenib in treating KRAS-mutant CRC in preclinical models. These findings are instrumental for KRAS-mutant CRC treatment aiming at activating TRIM21-mediated selective autophagic degradation of c-Myc.

Renal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. The kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. NBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. Our promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI.

The E-cadherin/β-catenin signaling pathway plays a critical role in the maintenance of epithelial architecture and regulation of tumor progression. Normally, E-cadherin locates on the cell surface with its cytosolic domain linking to the actin cytoskeleton through interaction with catenins. Although the nuclear localization of E-cadherin has been frequently observed in various types of cancers, little is known regarding the functional consequences of its nuclear translocation. Here, we showed that in colorectal cancer samples and cell lines, E-cadherin localized in the nucleus; and the nuclear localization was mediated through protein interaction with CTNND1. In the nucleus, E-cadherin was acetylated by CREB-binding protein at Lysine870 and Lysine871 in its β-catenin–binding domain, and the acetylation can be reversed by SIRT2. Acetylation of nuclear E-cadherin attenuated its interaction with β-catenin, which therefore released β-catenin from the complex, resulting in increased expression of its downstream genes and accelerated tumor growth and migration. Further study showed that acetylation level of nuclear E-cadherin had high prognostic significance in clinical colorectal samples. Taken together, our findings reveal a novel mechanism of tumor progression through posttranslational modification of E-cadherin, which may serve as a potential drug target of tumor therapy. Implications: This finding that acetylation of nuclear E-cadherin regulates β-catenin activity expands our understanding of the acetylation of E-cadherin promotes colorectal cancer cell growth and suggests novel therapeutic approaches of targeting acetylation in tumors.

Background and Aims: Spatial location of steatosis is closely related to the progression of metabolic dysfunction–associated steatohepatitis (MASH), and reports suggest lipid-associated macrophages (LAMs) facilitate this progression. However, the underlying mechanisms remain elusive. Approach and Results: Spatial transcriptomics (ST) data revealed a significant increase in myeloid cells and MASH-related genes in the hepatic periportal (PP) zone of MASH mice, suggesting a vital role of the PP zone in MASH progression. THRSP (SPOT14), involved in fatty acid synthesis, was markedly elevated in the livers of MASH patients and mice. Notably, CellPhoneDB analysis identified strong interactions between CD74 and macrophage migration inhibitory factor (MIF) within the Thrsp -high zone. Furthermore, Thrsp , Cd74 , Mif , Col3a1 , and LAMs markers were prominently colocalized in the hepatic PP zone of MASH mice, suggesting that Thrsp -mediated crosstalk in this region played a crucial role in MASH progression. Thrsp overexpression/knockout experiments confirmed that THRSP drove MASH progression by recruiting CD74 ⁺ LAMs mediated by MIF. Mechanistically, THRSP promoted hepatic palmitic acid (PA) synthesis, mainly by promoting hepatic de novo lipogenesis, and disturbing the binding of FASN–TRIM21, thereby inhibiting FASN ubiquitination. CD74 ⁺ LAMs were activated and recruited by chemokine-like MIF secreted from hepatocytes and macrophages stimulated with PA. Additionally, the compound C6, identified as a THRSP inhibitor, significantly ameliorated MASH in mice. Conclusions: Our study demonstrates that THRSP drives MASH progression by recruiting CD74 ⁺ LAMs mediated by MIF in the hepatic PP zone, providing novel insights into the spatial zonation and crosstalk between lipogenic hepatocytes and LAMs that may result in novel therapies for MASH.