Core Insights - The research conducted by Fudan University reveals a novel role of Acetyl-CoA as a "metabolic messenger" that directly regulates mitochondrial autophagy, providing a new therapeutic target for overcoming resistance to KRAS inhibitors in pancreatic cancer [1][7]. Group 1: Research Findings - The study highlights that during nutrient scarcity, Acetyl-CoA bypasses the well-known AMPK and mTOR pathways, directly signaling to mitochondria through the protein NLRX1 [1][2]. - The research team utilized CRISPR/Cas9 technology to identify NLRX1 as a key protein involved in this newly discovered signaling pathway [3][4]. - The interaction between Acetyl-CoA and NLRX1 was confirmed through a "molecular fishing" experiment, demonstrating a direct binding relationship [4][5]. Group 2: Implications for Cancer Treatment - The findings indicate that in nutrient-rich conditions, high levels of Acetyl-CoA inhibit mitochondrial autophagy by locking NLRX1 in a dormant state, while nutrient deprivation releases this inhibition, promoting autophagy [6][7]. - The study also uncovers a mechanism by which cancer cells develop resistance to KRAS inhibitors by activating mitochondrial autophagy in response to decreased Acetyl-CoA levels, suggesting a potential new treatment strategy [7][8]. - Targeting the Acetyl-CoA-NLRX1 axis could enhance the effectiveness of KRAS inhibitors, offering new hope for cancer patients facing treatment resistance [7][8].

Core Insights - The research published by Fudan University reveals a novel signaling function of Acetyl-Coenzyme A (AcCoA) in regulating mitophagy through the receptor NLRX1, independent of classical pathways like AMPK and mTOR [3][14][16] - This discovery provides new potential targets and strategies for overcoming resistance to KRAS inhibitors in cancer treatment [3][14][16] Group 1: Mechanism of AcCoA in Mitophagy - AcCoA levels decrease during nutrient deprivation, such as short-term fasting, leading to the activation of mitophagy [5][6] - NLRX1 is identified as a key mediator that directly binds to AcCoA, regulating its signaling role in mitophagy [8][11] Group 2: Experimental Validation - In animal models, fasting resulted in a significant decrease in AcCoA levels in tissues, correlating with increased mitophagy [11] - Supplementing with acetate or knocking out NLRX1 gene can block the fasting-induced mitophagy, indicating the critical role of AcCoA and NLRX1 in this process [11][12] Group 3: Implications for Cancer Treatment - The study indicates that KRAS inhibitors downregulate ACLY expression, reducing AcCoA levels and triggering NLRX1-dependent mitophagy, which may contribute to cancer cell resistance [14] - Short-term fasting may have dual effects in cancer treatment, potentially enhancing immune response while also promoting resistance through mitophagy [14][16] Group 4: Future Directions - Targeting the AcCoA-NLRX1 signaling axis may enhance cancer treatment efficacy and could have implications in various metabolic and neurodegenerative diseases [16]

Core Viewpoint - The research reveals a novel metabolic interaction between tumor-associated macrophages (TAM) and hepatocellular carcinoma (HCC) cells, identifying TAM as a source of acetate that drives HCC metastasis through the synthesis of acetyl-CoA [2][3][4]. Group 1: Research Findings - TAM secretes acetate, which is then taken up by HCC cells to support their acetate accumulation [3]. - Lactate produced by HCC cells activates lipid peroxidation-ALDH2 pathways in TAM, promoting the secretion of acetate [3]. - In a mouse model of HCC, knocking out the ALDH2 gene in TAM reduces acetate levels in HCC cells and decreases lung metastasis of HCC [3][4]. Group 2: Implications - The study positions TAM as a critical acetate supply source that drives HCC metastasis, suggesting potential intervention targets in the tumor microenvironment [2][4].

Core Viewpoint - The article discusses the advancements in the biosynthesis of 1,4-butanediol (BDO) through engineered Escherichia coli, highlighting the challenges and breakthroughs in creating a sustainable production method without antibiotics or inducers [2][3][7]. Group 1: BDO Production Challenges - BDO biosynthesis faces three main challenges: lack of natural BDO-producing microorganisms, significant carbon loss during synthesis, and high dependency on antibiotics and inducers, leading to increased costs [3]. Group 2: Engineering Breakthroughs - Researchers at Zhejiang University have developed a high-efficiency BDO synthesis strain by systematically engineering E. coli, resulting in a production of 0.1 g/L of BDO initially, which was later optimized to 0.82 g/L [6]. - The optimal enzyme combination for BDO production was identified, including enzymes from various bacteria, and a mutant enzyme variant was created that increased BDO yield by 11.19 times [6]. - By knocking out the pdhR gene, the researchers enhanced the conversion efficiency of pyruvate to acetyl-CoA, significantly reducing pyruvate accumulation and increasing BDO yield by 44% to 1.83 g/L [6]. Group 3: Antibiotic-Free Fermentation System - A significant advancement was the development of an antibiotic-free fermentation system, where the researchers utilized E. coli's native transcriptional regulatory elements to drive BDO synthesis without external inducers [7]. - The engineered strain B21-pT19 achieved a remarkable BDO production of 34.63 g/L in a 5 L reactor over 72 hours, maintaining stable yields across multiple fermentation batches without the need for antibiotics or inducers, marking the highest reported level of BDO production to date [7].