The role of E3s and DUBs in TAK1, ASK1 and mTOR signaling pathway in NAFLD. (1) TAK1, also known as MAP3K7, MAP3K7 promotes lipid deposition, inflammation, and pro-fibrotic factors by phosphorylating its downstream JNK/p38 signaling. The E3 ubiquitin ligases TRIM8, TRAF6, and TRAF3 can ubiquitinate and phosphorylate MAP3K7, activating the downstream JNK/p38 signaling cascade and aggravating liver steatosis, inflammation, and fibrosis. However, the deubiquitinases USP4, USP18, and CYLD can stop this process. Rhbdf2 can activate the MAP3K7 signaling pathway, but TRIM31 can block it through ubiquitination function, which degrades Rhbdf2 and phosphorylates MAP3K7. TRIM16 can also enhance the ubiquitination and degradation of phosphorylated MAP3K7 while inhibiting the downstream JNK/p38 signaling cascade. (2) ASK1, also known as MAP3K5, MAP3K5 promotes lipid deposition, inflammation, and pro-fibrotic factors by phosphorylating its downstream JNK/p38 signaling. The E3 ubiquitin ligases FBXW5 and TRAF6 can ubiquitinate and phosphorylate MAP3K5, activating the downstream JNK/p38 signaling cascade and aggravating liver steatosis, inflammation, and fibrosis. The deubiquitinase OTUB1 directly binds to TRAF6, boosting its deubiquitination, therefore decreasing TRAF6-mediated MAP3K5 ubiquitination and activation, and alleviating NASH. (3) The mTOR signaling pathway can modulate SREBP-1c transcription, inhibit autophagy, promote lipid accumulation, and activate NLRP3. E3 ubiquitin ligase FBW7 can enhance proteasome-mediated degradation of mTOR via ubiquitination, block downstream signal activation, and help avoid NAFLD. CUL4A, an E3 ubiquitin ligase, causes SHIP2 degradation through ubiquitination. The reduction of SHIP2 protein leads to the accumulation of PI3K, which then activates the downstream AKT signaling pathway, promoting adipogenesis, inflammation, and HCC progression. DDX5 may recruit the TSC1/2 complex to mTORC1, preventing downstream signal transduction, whereas the E3 ubiquitin ligase TRIM5 can enhance proteasome-mediated degradation of DDX5 via ubiquitination, reducing its inhibitory effect on mTORC1 signal transduction. MUL1, an E3 ubiquitin ligase, can promote AKT ubiquitination and degradation via BCAAs/BCKAs, inhibiting adipogenesis. CUL4B-DDB1, an E3 ubiquitin ligase, can enhance proteasome-mediated degradation of Raptor via ubiquitination, while inhibiting mTORC1 signaling transduction. USP7 deubiquitinates CREB and ZNF638, triggering the AKT signaling pathway. USP7 can also deubiquitinate Cleaved SREBP-1c, which exacerbates NAFLD.