ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/012/SRR27563512/SRR27563512_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/087/SRR27563487/SRR27563487_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/099/SRR27563499/SRR27563499_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/076/SRR27563476/SRR27563476_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/075/SRR27563475/SRR27563475_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/000/SRR27563500/SRR27563500_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/088/SRR27563488/SRR27563488_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/006/SRR27563506/SRR27563506_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/074/SRR27563474/SRR27563474_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/013/SRR27563513/SRR27563513_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/086/SRR27563486/SRR27563486_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/081/SRR27563481/SRR27563481_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/011/SRR27563511/SRR27563511_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/090/SRR27563490/SRR27563490_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/093/SRR27563493/SRR27563493_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/092/SRR27563492/SRR27563492_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/098/SRR27563498/SRR27563498_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/010/SRR27563510/SRR27563510_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/008/SRR27563508/SRR27563508_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/007/SRR27563507/SRR27563507_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/002/SRR27563502/SRR27563502_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/010/SRR27563510/SRR27563510_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/097/SRR27563497/SRR27563497_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/074/SRR27563474/SRR27563474_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/014/SRR27563514/SRR27563514_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/000/SRR27563500/SRR27563500_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/009/SRR27563509/SRR27563509_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/012/SRR27563512/SRR27563512_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/094/SRR27563494/SRR27563494_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/007/SRR27563507/SRR27563507_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/001/SRR27563501/SRR27563501_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/071/SRR27563471/SRR27563471_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/098/SRR27563498/SRR27563498_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/095/SRR27563495/SRR27563495_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/073/SRR27563473/SRR27563473_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/070/SRR27563470/SRR27563470_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/083/SRR27563483/SRR27563483_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/082/SRR27563482/SRR27563482_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/076/SRR27563476/SRR27563476_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/077/SRR27563477/SRR27563477_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/092/SRR27563492/SRR27563492_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/091/SRR27563491/SRR27563491_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/086/SRR27563486/SRR27563486_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/085/SRR27563485/SRR27563485_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/080/SRR27563480/SRR27563480_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/088/SRR27563488/SRR27563488_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/089/SRR27563489/SRR27563489_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/079/SRR27563479/SRR27563479_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/004/SRR27563504/SRR27563504_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/083/SRR27563483/SRR27563483_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/095/SRR27563495/SRR27563495_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/002/SRR27563502/SRR27563502_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/096/SRR27563496/SRR27563496_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/097/SRR27563497/SRR27563497_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/071/SRR27563471/SRR27563471_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/084/SRR27563484/SRR27563484_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/003/SRR27563503/SRR27563503_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/016/SRR27563516/SRR27563516_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/015/SRR27563515/SRR27563515_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/069/SRR27563469/SRR27563469_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/072/SRR27563472/SRR27563472_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/096/SRR27563496/SRR27563496_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/005/SRR27563505/SRR27563505_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/016/SRR27563516/SRR27563516_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/084/SRR27563484/SRR27563484_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/085/SRR27563485/SRR27563485_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/079/SRR27563479/SRR27563479_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/073/SRR27563473/SRR27563473_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/072/SRR27563472/SRR27563472_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/078/SRR27563478/SRR27563478_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/001/SRR27563501/SRR27563501_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/004/SRR27563504/SRR27563504_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/013/SRR27563513/SRR27563513_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/089/SRR27563489/SRR27563489_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/070/SRR27563470/SRR27563470_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/093/SRR27563493/SRR27563493_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/090/SRR27563490/SRR27563490_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/069/SRR27563469/SRR27563469_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/082/SRR27563482/SRR27563482_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/081/SRR27563481/SRR27563481_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/006/SRR27563506/SRR27563506_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/005/SRR27563505/SRR27563505_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/099/SRR27563499/SRR27563499_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/094/SRR27563494/SRR27563494_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/087/SRR27563487/SRR27563487_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/091/SRR27563491/SRR27563491_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/080/SRR27563480/SRR27563480_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/078/SRR27563478/SRR27563478_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/077/SRR27563477/SRR27563477_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/075/SRR27563475/SRR27563475_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/003/SRR27563503/SRR27563503_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/009/SRR27563509/SRR27563509_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/015/SRR27563515/SRR27563515_2.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/014/SRR27563514/SRR27563514_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/008/SRR27563508/SRR27563508_1.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/SRR275/011/SRR27563511/SRR27563511_1.fastq.gzprimaryOK200GenomicsEPFLhttps://www.ebi.ac.uk/ena/browser/view/PRJNA1065436xref:PubMed:39181211Recent findings reveal the importance of tryptophan-initiated de novo nicotinamide adenine dinucleotide (NAD+) synthesis in the liver, a process previously considered secondary to biosynthesis from nicotinamide. Here we show that inhibiting α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) promotes de novo NAD+ synthesis and reduces DNA damage ex vivo, in vivo and in human liver organoid (HLO) models. In mouse models of MASLD/MASH, de novo NAD+ biosynthesis is suppressed, and transcriptomic DNA damage signatures correlate with disease severity In humans, Mendelian randomization-based genetic analysis suggests a notable impact of genomic stress on liver disease susceptibility. Therapeutic inhibiting ACMSD in mice elevates liver NAD+ and reverses MASLD/MASH, mitigating fibrosis, inflammation and DNA damage. Similar outcomes are recapitulated in HLO models of steatohepatitis and DNA damage. Our findings highlight the benefits of ACMSD inhibition for boosting hepatic NAD+ and genomic protection, indicating its therapeutic promise in liver diseases marked by NAD+ and genomic stress. Overall design: To investigate the effect of ACMSD inhibition, mouse primary hepatocytes were treated with ACMSD inhibitor TLC-065 for 6, 12, and 24h. The effects of TLC-065 were tested in human liver organoid models of steatohepatitis.ENAfalseACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASHACMSD inhibition corrects fibrosis, inflammation, and DNA damage in MASLD/MASH2024-12-262024-09-25PRJNA1065436GSE25338039181211