Warning! Spoilers ahead for Sinister War #4
In the final issue of Marvel's Sinister War, it's confirmed that Mephisto has truly become Spider-Man's greatest villain. For a variety of reasons both old and new, the demon lord is responsible for more harm and damage to Peter Parker's life than any other foe, though it appears as though the worst has yet to come for the Webslinger. However, now that Spider-Man's battle with six Sinister Six teams has come to a close, Spider-Man is finally able to go after the demonic foe Kindred, who knows all about Peter Parker's past dealings with the demon lord himself.
In Sinister War #4 from writer Nick Spencer and artists Mark Bagley, Dio Neves, and Marcelo Ferreira, Spider-Man manages to survive the brutal and simultaneous attacks from the classic Sinister Six, the Savage Six, the Sinister Syndicate, the Superior Foes, the Wild Pack, and the dark Sinful Six. Just as it seemed Spider-Man couldn't hang on any longer fighting more than 30 of his villains all at once, Boomerang sacrificed himself to save Spider-Man, seeing as how they had been friends in the past. Furthermore, Doctor Octopus used a device he'd built in secret to destroy the centipedes Kindred inserted into all the villains' heads, which was forcing their compliance. Thankfully, it also knocked the villains out and Octavius permitted Spider-Man to leave while he still could to go after Kindred.
The issue ends with Mephisto lamenting the loss of all the souls he could have gained thanks to Kindred. However, he also tells Doctor Strange that the worst is yet to come for Spider-Man, foreshadowing the ultimate battle with Kindred where the truth will finally be revealed to Spider-Man about the chapters of his past Mephisto had made him forget in the past One More Day storyline, such as erasing his marriage to Mary Jane in order to save his Aunt May. However, more recent issues have revealed Mephisto being directly involved in the Green Goblin's creation, which also led to him owning Harry Osborn's soul before he would become Kindred. In this way, Mephisto truly is Spider-Man's greatest foe, having caused him the most pain through his various deals and manipulations.
When the literal Devil of the Marvel Universe says that Spider-Man is about to suffer a major loss, it can't be good. Peter Parker's final reckoning with Kindred is at hand, and it's already been teased that there's more to the demonic villain and agent of Mephisto than his just being the version of Harry that was dead prior to the One More Day retcon. Furthermore, due to recent previews hinting at Parker's death ahead of his clone Ben Reilley taking over as Spider-Man, it certainly seems as though the final issues of Nick Spencer's Amazing Spider-Man won't be issues to be missed.
In any case, while Mephisto is a scourge and major villain in the Marvel Universe at large, he's very much a major foe for Spider-Man in particular and perhaps his greatest considering all the suffering and pain he's caused him over the years. Furthermore, all the damage brought on by Norman and Harry Osborn should be attributed to Mephisto as well, seeing as how he created them both. Despite the likeliness that it will end with his death, here's hoping Spider-Man can finally see Mephisto receiving some justice as Nick Spencer's run comes to a close in just a few issues.