SERPINA1/AAT/alpha-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1 E342K /ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury. Both proteasome and macroautophagy/autophagy pathways are responsible for disposal of SERPINA1 E342K /ATZ after it accumulates in the ER. However, the mechanisms by which SERPINA1 E342K /ATZ is selectively degraded by autophagy remain unknown. Here, we showed that ER membrane-spanning ubiquitin ligase (E3) SYVN1/HRD1 enhances the degradation of SERPINA1 E342K /ATZ through the autophagy-lysosome pathway. We found that SYVN1 promoted SERPINA1 E342K /ATZ, especially Triton X 100-insoluble SERPINA1 E342K /ATZ clearance. However, the effect of SYVN1 in SERPINA1 E342K /ATZ clearance was impaired after autophagy inhibition, as well as in autophagy related 5 ( atg5 ) knockout cells. On the contrary, autophagy induction enhanced SYVN1-mediated SERPINA1 E342K /ATZ degradation. Further study showed that SYVN1 mediated SERPINA1 E342K /ATZ ubiquitination, which is required for autophagic degradation of SERPINA1 E342K /ATZ by promoting the interaction between SERPINA1 E342K /ATZ and SQSTM1/p62 for formation of the autophagy complex. Interestingly, SYVN1-mediated lysine 48 (K48)-linked polyubiquitin chains that conjugated onto SERPINA1 E342K /ATZ might predominantly bind to the ubiquitin-associated (UBA) domain of SQSTM1 and couple the ubiquitinated SERPINA1 E342K /ATZ to the lysosome for degradation. In addition, autophagy inhibition attenuated the suppressive effect of SYVN1 on SERPINA1 E342K /ATZ cytotoxicity, and the autophagy inducer rapamycin enhanced the suppressive effect of SYVN1 on SERPINA1 E342K /ATZ-induced cell apoptosis. Therefore, this study proved that SYVN1 enhances SERPINA1 E342K /ATZ degradation through SQSTM1-dependent autophagy and attenuates SERPINA1 E342K /ATZ cytotoxicity.