In many episodes of The Simpsons, Lisa's primary motivation has been to become popular or develop lasting friendships. While she's an enthusiastic and brilliant girl, Lisa is often portrayed as being lonely and disconnected from her peers -- finding more in common with Disney villains than most kids her age. A fan theory for the long-running show suggests this might be partly her fault, however. While Lisa might be ostracized on a lot of levels throughout The Simpsons, elements of her own personality might explain why she doesn't have major friendships of her own.
Throughout the course of The Simpsons, Lisa has been frequently portrayed as an overlooked and lonely little girl, desperate for friendship. Despite her intellect and sweet deposition, it's not uncommon for episodes to focus on Lisa's inability to form lasting bonds. While she may make a new friend like Alison in Season 6's "Lisa's Rival" or Isabella in Season 25's "The Kid Is All Right," by the next episode she's alone again. Her most consistent peers are often shown to be openly antagonistic to her (like Sherri and Terri), while her closest friend -- Janey -- has never been given a spotlight of her own in the show.
As noted by a theory in the WMG page of TVTropes for the series, Lisa's inability to maintain friendships with other girls might not be as one-sided as it's presented. While other girls are often shown picking on Lisa, other episodes, like Season 10's "Lard of the Dance," see Lisa fitting in easily with the other girls her age. Occasional Bart love interests Sherri and Terri can even been seen in some episodes opening up to Lisa, as in "Season 17's "The Last of the Red Hat Mamas," only to be rebuffed.
The theory argues that the other girls may have stopped hanging out with Lisa due to her own behavior and actions. Lisa's frequent crusades and personal missions drive her, but also more or less cut her off from anyone else who would want to spend time with her, and the few times she does become popular, as in Season 6's "Bart of Darkness" or Season 27's "Teenage Mutant Milk-Caused Hurdles," she becomes stuck-up and aggressive instantly.
Lisa always focuses on how lonely she is and how no one wants to share her interests, but Lisa is rarely shown trying to understand or engage the interests of her peers. Episodes like Season 18's "Marge Gamer" have shown Lisa trying to find her "new thing" in soccer, only to abandon any new passion just as quickly as she found it. When she's offered a spot on the peewee football team in Season 9's "Bart Star," Lisa isn't shown wanting to play for friendship or develop bonds with her teammates, but only so she can be the focus of attention.
The theory argues that Lisa ends up inviting much of this loneliness on herself, turning down potential friendships because people don't share her passions or can't keep her attention. This would offer a clever way to explain in-universe why Lisa never maintains her friendships with the various guest stars who've played her new friends.
In the real world, it's because these characters are often portrayed by celebrities who can't appear on the show regularly, but in universe, it could be the result of the other girls getting tired of Lisa's constant missions to save the world or episodic obsessions with a new passion. It adds a layer of complexity to Lisa, typically held up as one of the show's moral centers -- giving her a character flaw that reinforces the idea that Lisa just needs to grow up and find people she can relate with to be happy.
While the entire town of Springfield may admire her, every visit to a possible future has implied Lisa will leave the town and any friends who remained there when she grows up. It's an interesting concept that plays into Lisa's established growth as the series has gone on, and even adds some layers to the other girls who often seem to ignore Lisa.