Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), which has gradually been replaced by MASLD in recent years because the latter reflects the multifactorial metabolic origins of steatotic liver disease more accurately [1]. MASLD is one of the most prevalent complications associated with obesity, affecting approximately one-quarter of the global population, which can progress to liver fibrosis and cirrhosis, posing a significant threat to human health [2]. Traditional management strategies for MASLD include lifestyle interventions, medications, and surgical options [3], yet clinicians continue to seek more advanced therapeutic approaches. The currently most recognized pathogenesis mechanism of MASLD is the ‘multiple shock theory’. Hepatic lipotoxicity is mediated by excessive fat beyond metabolic capacity accumulated in liver in the form of triglycerides with simultaneously high level of free fatty acid (FA) production. Lipotoxicity consequently triggers endoplasmic reticulum stress (ERS) and mitochondrial dysfunction [[4], [5], [6]], which jointly aggravated further lipid accumulation and hepatocytes injury, even cell death. Most studies in the past tend to explain the roles of the two organelles in MASLD separately, however, a growing body of research proves that the functional homeostasis of mitochondria and endoplasmic reticulum (ER) is actually interdependent [7].

Mitochondria associated membranes (MAMs) refer to dynamic lipid raft-like domains located between mitochondria and ER, which play a critical role in several cellular processes [[8], [9], [10]]. Specifically, MAMs sustain mitochondrial function by modulating mitochondrial dynamics [11], energy metabolism [12], reactive oxygen species (ROS) production [13] and mitophagy [14]. On the other hand, MAMs aggravate cell apoptosis and ferroptosis during ERS by mediating the exchange of ROS and calcium [[15], [16], [17]], suggesting that MAMs constitute a crosstalk between ER and mitochondrial homeostasis. MAMs disruption has been implicated in various metabolic diseases, including neurodegenerative disorders, type 2 diabetes mellitus (T2DM), diabetic kidney, and MASLD [[18], [19], [20]], highlighting its potential as a therapeutic target.

Mitofusin 2 (Mfn2), a transmembrane dynamic protein located at the outer membrane of mitochondria, is crucial in modulating mitochondrial fusion and keeping mitochondrial homeostasis [21], and Mfn2 downregulation has been observed in the livers of MASLD individuals [[22], [23], [24]]. PRKR-like endoplasmic reticulum kinase (PERK) locates at the ER membrane as one of the classical sensors of unfolded protein reaction (UPR) [25], which mediates cell failure via activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) [26]. Mfn2 has been reported to interacts with PERK at MAMs and protect cells from ERS by negatively regulating UPR activation [27,28]. However, the effect of MAMs modulation via the Mfn2/PERK/CHOP pathway has not been studied in MASLD.

Photobiomodulation (PBM) refers to the biological processes activated by photons from specific wavelengths of light or laser without causing photothermal damage [29]. PBM has been reported to improve hyperglycemia and hyperlipidemia by stimulating insulin signaling in different tissues, including skeletal muscles, liver and adipose tissue [[30], [31], [32]], and PBM can also relieve the inflammatory filtrate in adipose tissue of obese mice [33], suggesting its potential in treating metabolic diseases, although the mechanism has not been fully elucidated. In this study, we demonstrated that PBM using a 650 nm diode laser ameliorated the high-fat-diet (HFD)-induced MASLD in mice and the FA-induced lipotoxicity in HepG2 cells and explored the underlying mechanism.