Considered a chance for State of Origin selection before the series began, centre Campbell Graham will now miss up to two months of football after sustaining a facial fracture in the win over Parramatta last week.
Hame Sele (hamstring) also comes out of the side, replaced in the front row by Tom Burgess, while Mark Nicholls has been named to start at lock against Newcastle despite failing his head injury assessment against the Eels.
The Rabbitohs would have been counting on Graham to help neutralise explosive Knights centre Bradman Best, who returns from an elbow injury for Friday's game, but will have to be content with Taane Milne in the centres.
Newcastle's Jayden Brailey has been named to start on the bench for his first game since rupturing an Achilles tendon at training in January.
Elsewhere, Melbourne coach Craig Bellamy has cut Jayden Nikorima's fairytale return to the NRL short - Nikorima started at five-eighth last week for his first game since 2016 but has been pushed to 18th man for Thursday's intriguing clash between the Storm and Cronulla.
Nick Meaney will line up at five-eighth in place of Cameron Munster, who continues to recover from the shoulder injury he sustained in State of Origin game two.
Sharks playmaker Nicho Hynes is free to face his old side after relinquishing 18th-man duties for Origin III.
Wests Tigers utility Adam Doueihi has forced his way into the starting side for the first time since recovering from an ACL injury last month.
Doueihi will line up at centre against Parramatta, allowing the beleaguered Luke Brooks to keep his spot at five-eighth, as the Tigers chase their first win under interim coach Brett Kimmorley.
Captain James Tamou returns to the front row, having missed last week's loss to the Warriors with a calf injury, while NSW Under 19s Origin player Justin Matamua makes his NRL debut for the Tigers.
Last year's NSW Cup Player of the Year Zac Hosking also gets his first taste of the NRL at second row for Brisbane in their clash with St George Illawarra.
The Broncos are missing a large contingent of their forward pack to either State of Origin duty or injury so also welcome Ryan James, Keenan Palasia and Kobe Hetherington into the starting side.
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