Ripe with playmakers, the San Francisco 49ers present a multitude of challenges for the Tennessee Titans and their No. 10-ranked defense.

However, the area the 49ers’ offense excels in most just so happens to be the area the Titans’ defense thrives in as well: the run game. 

The No. 7 run offense in the NFL, San Francisco averages 126.6 yards rushing per game. What makes the 49ers’ run game so dangerous is the multiple looks they give with multiple players, including receiver Deebo Samuel out of the backfield. 

The 49ers also boast the best left tackle in the NFL in Trent Williams and the No. 4-ranked offensive line in the league, according to Pro Football Focus. Fullback Kyle Juszczyk is also the second-most-used FB in run protection in the NFL.

But if there were a team custom built to stop such a unique rushing attack it would be the Titans, who have the No. 2-ranked run defense in the league and rank second in run-stop win rate (33 percent).

“Their strength is running the ball, and our strength is stopping the run,” Titans defensive tackle Jeffery Simmons said. “It’s kind of one of those strength-on-strength things. It’s going to come down to who’s going to be the most physical and the team that wants it the most.”

Elijah Mitchell, who ranks 14th in the NFL with 759 yards rushing, was a non-participant in practice both Monday and Tuesday. It’s not known whether he’ll play Thursday, but if he can’t go, Jeff Wilson Jr. has proven he’s more than capable of taking the lead-back role.

Against the Atlanta Falcons on Sunday, Wilson Jr. had 110 yards and a touchdown on 21 carries. It was his second straight game with double-digit rush attempts, and he’s carried the ball 10 or more times in four of the five games he’s played this season.

Samuel, San Francisco’s second-leading rusher, has a rushing touchdown in five straight games, and he’s averaged nearly 50 yards rushing per game over that span. And by the way, he’s also sixth in the NFL in receiving yards (1,088).

“It is a really good scheme,” Titans head coach Mike Vrabel said. “I think the offensive line does a fantastic job. They are well-coached. The tight ends block well. … They mix in Samuel, Mitchell, Wilson; they have a good scheme. They attack you at all different levels. Zone, gap scheme, misdirection. They do a fantastic job.”

Working in the Titans’ favor, however, is the fact that really no one has been able to run on them all year. They’ve allowed just one 100-yard rusher all season — Jacksonville’s James Robinson in Week 5.

Through 14 games, the Titans allow the second-fewest rush yards per game (86.9), the third-fewest yards per carry (3.9) and the fourth-fewest first downs via run (74).

In fact, Tennessee has fared pretty well against top-20 running backs this year:

No. 1 — Jonathan Taylor: 16 carries, 70 yards (Week 3); 10 carries, 64 yards (Week 8)

No. 6 — Najee Harris: 12 carries, 18 yards

No. 15 — James Robinson: 18 carries, 149 yards (Week 5); 6 carries, 4 yards (Week 14)

No. 16 — Damien Harris: 11 carries, 40 yards

No. 17 — James Conner: 16 carries, 53 yards

“These guys want to run the ball,” Simmons continued. “You can see on film that these guys want to try to knock you off the ball. The last two weeks, we have been stopping the run. That’s why I said it’s strength on strength.”

Follow Michael Gallagher on Twitter @MGsports_