The geopolitical undertones weigh heavy on the meeting, along with twin threats from a viral pandemic and ongoing tensions with rocket-firing Iranian-backed rogue groups.
For Iraq's dwindling Christian minority, a show of solidarity from al-Sistani could help secure their place in Iraq after years of displacement and, they hope, ease intimidation from Shiite militiamen against their community.
Iraqi officials in government, too, see the meeting's symbolic power as does Tehran.
The 90-year-old al-Sistani has been a consistent counterweight to Iran's influence.
With the meeting, Francis is implicitly recognizing him as the chief interlocutor of Shiite Islam over his rival, Iranian Supreme Leader Ali Khamenei. News of the meeting heightened long-standing rivalries between the Shiite seminaries of Najaf and Iran's city of Qom over which stands at the center of the Shiite world.
It will be a private visit without precedent in history, and it will not have an equal to any previous visits, said a religious official in Najaf, involved in the planning.
For the Vatican, it was a meeting decades in the making, one that eluded Francis' predecessors.
Najaf did not make it easy, said one Christian religious official close to the planning from the Vatican side, speaking on condition of anonymity because of the visit's delicacy.
In December, Louis Sako, the patriarch of Iraq's Chaldean Catholic Church told The Associated Press the church was trying to schedule a meeting between Francis and the ayatollah. It was included in the first draft of the program, but when the (Vatican) delegation visited Najaf, there were problems, he said, without elaborating.
The church kept insisting.
We know the importance and impact of Najaf in the Iraqi situation, Sako said. What value would the pope's message of coexistence in Iraq have, they determined, if he did not seek the support of its most powerful and respected religious figure?
Sako finally confirmed the meeting in January, weeks after the pontiff's itinerary had been assembled.
Rarely does al-Sistani weigh in on governance matters. When he has, it has shifted the course of Iraq's modern history.
An edict from him provided many Iraqis reason to participate in the January 2005 elections, the first after the 2003 US-led invasion.
His 2014 fatwa calling on able-bodied men to fight the Islamic State group massively swelled the ranks of Shiite militias. In 2019, as anti-government demonstrations gripped the country, his sermon lead to the resignation of then-prime minister Adil Abdul-Mahdi.
The Vatican's hope was that Francis would sign a document with al-Sistani pledging human fraternity, just as he did with Sunni Islam's influential grand imam of al-Azhar, Ahmed el-Tayeb, based in Egypt.
The signature was among many elements the two sides negotiated over extensively. In the end, Shiite religious officials in Najaf told the AP a signing was not on the agenda, and al-Sistani will issue a verbal statement instead.
Each minute of Saturday's meeting will likely unfold as meticulously as a scripted stage play.
The 84-year-old pontiff's convoy will pull up along Najaf's busy column-lined Rasool Street, which culminates at the Imam Ali Shrine, one of the most revered sites in the world for Shiites.
To the side is an alleyway too narrow for cars. Here, Francis will walk the 30 meters (yards) to al-Sistani's modest home, which the cleric has rented for decades. Waiting to greet him at the entrance will be al-Sistani's influential son, Mohammed Ridha.
Inside, and some steps to the right, the pontiff will come face to face with the ayatollah.
Each will make a simple gesture of mutual respect.
Francis will remove his shoes before entering al-Sistani's room.
Al-Sistani, who normally remains seated for visitors, will stand to greet Francis at the door and walk him to an L-shaped blue sofa, inviting him to take a seat.
This has not taken place by his Eminence with any guest before, said a Najaf religious official.
He will stand despite his fragile health, said the religious officials. Since fracturing his thigh last year, the cleric has been firmly ensconced indoors. Francis suffers from sciatica.
The Pope will be offered tea.
(Only the headline and picture of this report may have been reworked by the Business Standard staff; the rest of the content is auto-generated from a syndicated feed.)
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