Sqstm1, also known as p62, is a multifunctional scaffolding protein and a classical selective autophagy receptor [1,2,7]. It serves as an essential adaptor in selective autophagy, identifying and delivering specific organelles and protein aggregates to autophagosomes for degradation [2]. It is involved in various signaling pathways and plays a crucial role in maintaining cellular proteostasis, which is essential for somatic maintenance [7]. Genetic models such as knockout (KO) or conditional knockout (CKO) mouse models are valuable for studying its functions.

In vascular smooth muscle cells (VSMCs), Sqstm1 deficiency mimicked the phenotype of Ppargc1a depletion, presenting reduced autophagy and increased senescence both in vitro and in vivo. This suggests that Sqstm1 is a major regulator of autophagy and senescence in VSMCs and that the mitochondrial regulator PPARGC1A upregulates autophagy and reduces senescence through a Sqstm1 -dependent mechanism [3].

In the liver, liver-specific sqstm1-knockout mice showed that the SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity, indicating its importance in protecting the liver from lipotoxicity-related damage [4].

Disrupting the TRIB3-SQSTM1 interaction in mouse models of hepatic fibrosis restored autophagic flux in hepatocytes and hepatic stellate cells (HSCs), protecting against experimentally induced hepatic fibrosis [5].

Knockdown of Sqstm1 in the epidermis of a mouse model inhibited autophagy and delayed wound healing, highlighting its role in diabetic skin wound healing [6].

In conclusion, Sqstm1 is a pivotal player in selective autophagy, with its functions spanning across multiple biological processes such as autophagy regulation, senescence control, and protection against lipotoxicity and fibrosis. The use of KO/CKO mouse models has significantly contributed to understanding its role in diseases related to vascular senescence, fatty liver disease, hepatic fibrosis, and diabetic skin wound healing, providing insights into potential therapeutic strategies targeting these disease areas.