Short answer- possibly.

Splenda (also known as sucralose) is one of the most popular non-nutritive sweeteners worldwide. It is much sweeter than sugar, but little is absorbed into the body.

Non-alcoholic fatty liver (NAFL) occurs in the context of a diet containing excess calories, especially if the diet contains a lot of fructose. Fructose is one half of the duo, that with glucose, forms table sugar (sucrose). Of the two, fructose tastes the sweetest. Whereas glucose serves as a primary fuel by most cells of the body, fructose is only used by the liver. In the natural world, fructose is mostly found in fruit, and the amount of fructose supplied by a normal number of servings of fruit is sufficient for the liver’s needs. 

However, in the last 30 years, food and beverage companies have been adding fructose to corn syrup as a sweetener for many foods.  At the same time, consumers have preferred sweeter tastes in beverages, including sodas and fruit juices. This has led to a dramatic increase in the amount of fructose consumed, providing far more fructose in the diet than the liver needs. Not surprisingly, metabolic diseases, including non-alcoholic fatty liver disease, have become epidemic. High amounts of fructose in the diet have been identified as a major culprit (Jensen 2018). 

What happens is that when the fructose available exceeds the needs of the liver, the liver converts it into fat for storage. Some of these fats enter the circulation and are stored in adipose tissue. But some of the fat can accumulate in liver cells and impair their functions, causing NAFL. Over time, a condition called non-alcoholic hepatic steatohepatitis (NASH) can develop, in which the fatty tissue becomes inflamed. This condition can lead to liver cirrhosis, and then to liver cancer. 

The incidence of NAFL and NASH has been increasing since 1980, and they are now the second-leading cause of the need for liver transplants. Fortunately, weight loss, switching to a healthy, low-sugar diet, and getting exercise can halt or reverse the damage to the liver (Abenavoli 2019).

Because of the link between sugar and NAFL, substituting non-nutritive sweeteners, such as Splenda, for sugar in drinks or foods may be a way to reduce the sugar in the diet but still get that sweet taste. 

As yet, there are no direct studies that have investigated the effects of Splenda (sucralose), on NAFL in humans. Studies of an association of sucralose with fatty liver in mice and rats have had mixed results. 

On the one hand, studies of mice and humans looking at weight and metabolic dysregulation, including insulin resistance, typically find no effects of sucralose. Some studies report beneficial effects, especially in overweight subjects consuming a high-fat diet (Higgins & Mattes 2019; Pino-Seguel et al.2022). Studies generally were short-term, however, and it is still unclear what would be the effects of long-term chronic consumption. Splenda is relatively new compared to saccharine and aspartame, and there is a lack of studies investigating the effects of long-term or chronic use of it.

On the other hand, mice fed sucralose developed fatty liver, and this effect was associated with changes in populations of gut microbes (Shi et al. 2021). Gut microbes are consistently disrupted in NAFL, and there are now several hypotheses about how this could contribute to the development of fatty liver and liver inflammation (Shi 2021; Wu 2022). Microbes in the gut may be particularly susceptible to any effects of sucralose because little sucralose is absorbed into the body, leaving more in the gut to influence the microbes. It is not worked out, however, what kinds of effects on microbes Splenda might have, but it does seem to induce the production of microbial substances found to influence NAFL (Shi 201)

Overall, based on the current literature, Munteaunu & Schwartz (2023) advise against people who have NAFL using sucralose/Splenda.